Processes for preparing toll-like receptor modulator compounds

ABSTRACT

The present disclosure provides methods for preparing (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol or a salt thereof and related key intermediates.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/911,643, filed Jun. 25, 2020, which claims priority to U.S.Provisional Application No. 62/868,662, filed Jun. 28, 2019, each ofwhich is incorporated herein in its entirety for all purposes.

BACKGROUND OF THE DISCLOSURE

Toll-like receptor (TLR) family plays a fundamental role in pathogenrecognition and activation of innate immunity. Toll-like receptor 8(TLR-8) is predominantly expressed by myeloid immune cells andactivation of this receptor stimulates a broad immunological response.Agonists of TLR-8 activate myeloid dendritic cells, monocytes,monocyte-derived dendridic cells and Kupffer cells leading to theproduction of proinflammatory cytokines and chemokines, such asinterleukin-18 (IL-18), interleukin-12 (IL-12), tumor necrosisfactor-alpha (TNF-α), and interferongamma (IFN-γ). Such agonists alsopromote the increased expression of co-stimulatory molecules such asCD⁸⁺ cells, major histocompatibility complex molecules (MAIT, NK cells),and chemokine receptors.

Collectively, activation of these innate and adaptive immune responsesinduces an immune response and provides a therapeutic benefit in variousconditions involving autoimmunity, inflammation, allergy, asthma, graftrejection, graft versus host disease (GvHD), infection, cancer, andimmunodeficiency. For example, with respect to hepatitis B, activationof TLR8 on professional antigen presenting cells (pAPCs) and otherintrahepatic immune cells is associated with induction of IL-12 andproinflammatory cytokines, which is expected to augment HBV-specific Tcell responses, activate intrahepatic NK cells and drive reconstitutionof antiviral immunity. See e.g. Wille-Reece, U. et al., J Exp Med 203,1249-1258 (2006); Peng, G. et al., Science 309, 1380-1 384 (2005); Jo,J. et al., PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., JBiol Chem 288, 317 15-3 1727 (2013).

Given the potential to treat a wide array of diseases, potent andselective modulators of TLR-8 that have reduced potential for off targetliabilities are particularly desirable. Toll-like receptor modulatorcompounds, such as diamino pyrido[3,2-d]pyrimidine compounds and methodsof making them have been disclosed in WO 2016/141092. However, thereremains a need for methods of preparing diamino pyrido[3,2-d]pyrimidinecompounds.

BRIEF SUMMARY OF THE DISCLOSURE

In one embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula III:

-   -   -   or a salt thereof, a compound having the formula            PG-NHC(═NH)NH₂ or a salt thereof, a first base, and a first            solvent to form a compound of Formula II:

-   -   -   or a salt thereof; and

    -   b) forming a second reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        second solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ are each independently hydrogen, F, Cl,        CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen or methyl;        R⁵ is C₃₋₆ alkyl; X is F, Cl, Br, I, or OTs; and PG is an amino        protecting group.

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula III:

-   -   -   or a salt thereof, a compound having the Formula            PG-NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent to form a            compound of Formula II:

-   -   -   or a salt thereof; and

    -   b) forming a second reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        second solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ are each independently hydrogen, F, Cl,        CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen or methyl;        R⁵ is C₃₋₆ alkyl; X is Cl, Br, I, or OTs; and PG is an amino        protecting group.

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, the method including:

-   -   a4) forming a seventh reaction mixture including a compound of        Formula VIIIb:

-   -   -   or a salt thereof, oxalyl chloride, N,N-dimethylformamide,            2-methyltetrahydrofuran to form a compound of Formula VIIb:

-   -   -   or a salt thereof;

    -   a3) forming a sixth reaction mixture including the compound of        Formula VIIb or the salt thereof, a compound of Formula VIb:

-   -   -   aqueous potassium carbonate, 2-methyltetrahydrofuran, and            water to form a compound of Formula Vb:

-   -   -   or a salt thereof;

    -   a2) forming a fourth reaction mixture including the compound of        Formula Vb or the salt thereof, thionyl chloride, and        2-methyltetrahydrofuran to form a compound of Formula IVb-1:

-   -   -   or a salt thereof;

    -   a1) forming a third reaction mixture including the compound of        Formula IVb-1 or the salt thereof, aqueous sodium hydroxide,        tetra-n-butylammonium hydrogensulfate, and        2-methyltetrahydrofuran to form a compound of Formula IIIb:

-   -   -   or a salt thereof;

    -   a) forming a first reaction mixture including the compound of        Formula IIIb or the salt thereof, a compound a compound of        Formula IXa wherein n is from 0 to 1:

-   -   -   Cu(II) acetate, potassium phosphate tribasic, cysteine,            2-methyltetrahydrofuran, and acetonitrile to form a compound            of Formula IIb:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture including the compound of        Formula IIb or the salt thereof, trifluoroacetic acid, and        dichloromethane to prepare a trifluoroacetic acid salt of the        compound of Formula Ib:

-   -   c) forming a ninth reaction mixture including the        trifluoroacetic acid salt of the compound of Formula Ib, sodium        hydroxide, ethanol, and water to provide the compound of Formula        Ib in a neutral form.

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula II:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula V:

-   -   -   or a salt thereof, a compound having the Formula            PG-NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent to form the            compound of Formula II, or a salt thereof,            wherein R¹, R², and R³ can each independently be hydrogen,            F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be            hydrogen or methyl; R⁵ can be C₃₋₆ alkyl; X can be F, Cl,            Br, I, or OTs; and PG can be an amino protecting group.

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, comprising:

-   -   a) forming a first reaction mixture comprising a compound of        Formula III:

-   -   -   a compound having the Formula H₂NC(═NH)NH₂ or a salt            thereof, a first base, and a first solvent to form the            compound of Formula I or the salt thereof,            wherein R¹, R², and R³ can each independently be hydrogen,            F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be            hydrogen or methyl; R⁵ can be C₃₋₆ alkyl; and X can be F,            Cl, Br, I, or OTs.

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula XVIII:

or a salt thereof, comprising:

-   -   a) forming a first reaction mixture comprising a compound of        Formula XV:

-   -   -   a compound of Formula XVI-1:

-   -   -   or a salt thereof, a compound having the Formula            R⁷—NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent, to form the            compound of Formula XVIII or the salt thereof,            wherein R¹, R², and R³ are each independently hydrogen, F,            Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen or            methyl; R⁵ is C₁₋₆ alkyl; R⁶ is hydrogen, OH, or O-PG1; R⁷            is hydrogen or PG; X and X¹ are each independently F, Cl,            Br, I, or OTs; PG is an amino protecting group; and PG1 is a            hydroxy protecting group.

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula XI:

-   -   -   or a salt thereof, a compound of Formula VI:

-   -   -   or a salt thereof, a first base, and a first solvent to form            a compound of Formula X:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture including the compound of        Formula IX or the salt thereof, a compound of PG-NH₂ or a salt        thereof, a second base, and a second solvent to form a compound        of Formula II:

-   -   -   or a salt thereof; and

    -   b) forming a third reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        third solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ are each independently hydrogen, F, Cl,        CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen or methyl;        R⁵ is C₃₋₆ alkyl; and PG is an amino protecting group.

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, the method comprising:

-   -   a) forming a first reaction mixture comprising a compound of        Formula XIb:

-   -   -   or a salt thereof, a compound of Formula VIb:

-   -   -   N,N-diisopropylethylamine, 2-methyltetrahydrofuran, and            isopropyl acetate to form a compound of Formula Xb:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture comprising the compound of        Formula Xb or the salt thereof, 2,4-dimethoxybenzylamine,        potassium carbonate, 2-methyltetrahydrofuran, and isopropyl        acetate to form a compound of Formula IIb:

-   -   -   or a salt thereof; and

    -   c) forming a third reaction mixture comprising the compound of        Formula IIb or the salt thereof, trifluoroacetic acid, and        dichloromethane to prepare a trifluoroacetic acid salt of the        compound of Formula Ib:

and

-   -   d) forming a fourth reaction mixture comprising the        trifluoroacetic acid salt of the compound of Formula Ib, sodium        hydroxide, ethanol, and water to provide the compound of Formula        Ib in a salt-free form.

In another embodiment, the present disclosure provides a compound ofFormula III:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; and X is F, Cl, Br, I, or OTs.

In another embodiment, the present disclosure provides a compound ofFormula III:

or a salt thereof, wherein R¹, R², and R are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; and X is Cl, Br, I, or OTs.

In another embodiment, the present disclosure provides a compound ofFormula IV:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; X is F, Cl, Br, I, or OTs; and AG¹ is Cl, Br,OSO₃H, OSO₃ ⁻, OMs, OTs, or OTf.

In another embodiment, the present disclosure provides a compound ofFormula IV:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; X is F, Cl, Br, I, or OTs; and AG¹ is Cl, Br,OMs, OTs, or OTf.

In another embodiment, the present disclosure provides a compound ofFormula V:

or a salt thereof, wherein R¹, R, and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; and X is F, Cl, Br, I, or OTs, provided thatthe compound of Formula V is not3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.

In another embodiment, the present disclosure provides a compound ofFormula V:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; and X is Cl, Br, I, or OTs, provided that thecompound of Formula V is not3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.

In another embodiment, the present disclosure provides a compound ofFormula XII.

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; and R⁶ and R⁷ areeach independently hydrogen, C₁₋₄ alkyl, or C₃₋₆ cycloalkyl, or R⁶ andR⁷ are combined to form a 3-6 membered N-linked heterocycloalkyl,optionally having an additional 1-2 heteroatoms selected from O and S,provided that at least one of R¹, R², and R³ is F, Cl, CN, CF₃, C₁₋₃alkyl, or C₁₋₃ alkoxy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the preparation of the compound of Formula Ib via atransition-metal mediated coupling reaction of(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole(IIIb) with a protected guanidine compound provides(R)-2-((2-((3,4-dimethylbenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Ib), which is then deprotected to form(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Ib).

FIG. 2 shows the preparation of the compound of Formula Ib via twosequential nucleophilic aromatic substitution reactions of2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine (XIb) to provide(R)-2-((2-((3,4-dimethylbenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Ib), which is then deprotected to form(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Ib).

FIG. 3A shows the preparation of the compound of Formula VIb via stepsof condensation, alkylation/hydrolysis, salt formation, enzymaticresolution, BOC protection, reduction, and deprotection/TsOH saltformation. FIG. 3B shows an alternative method for preparing isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate.

FIG. 4 shows the preparation of the compound of Formula VIb via steps ofcyclocondensation, nucleophilic addition, reduction, andhydrogenolysis/TsOH salt formation.

FIG. 5A shows the preparation of the compound of Formula VIIIb via stepsof halogen exchange, cyanation, and hydrolysis. FIG. 5B shows analternative method for preparing 3-bromo-5-fluoro-2-iodopyridine.

FIG. 6 shows the preparation of the compound of Formula VIIIb via stepsof amidation, bromination, and hydrolysis.

FIG. 7A shows the preparation of the compound of Formula XIb via stepsof cyanation, cyclization with carbon dioxide, and chlorination. FIG. 7Bshows an alternative method for preparing7-fluoropyrido[3,2-d]pyrimidine-2,4-diol via steps of oxidation andcyclization with triphosgene.

FIG. 8 shows the preparation of the compound of IIIb from the compoundof Formula IIb via steps of sulfonation, ion-exchange, and cyclization.

FIG. 9 shows the preparation of the compound of Formula IIb from3,5-difluoropicolinic acid (VIIIb-1) via a coupling reaction of(R)-2-(3-fluoro-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole(IIb-1) with a protected guanidine compound.

FIG. 10 shows the preparation of the compound of Formula IIb via atransition-metal mediated coupling reaction of(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (Vb)with a protected guanidine compound.

FIG. 11 shows the preparation the compound of Formula Ib via a directcoupling reaction of(R)-2-(3-fluoro-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole(IIIb-1) with a guanidine salt.

FIG. 12 shows the preparation the compound of Formula Ib via acondensation reaction of 2-bromo-3,5-difluoropyridine,(R)-2-isocyano-2-methylhexan-1-ol, and a guanidine salt.

FIG. 13 shows the preparation of isopropyl 2-amino-2-methylhexanoatefrom hexan-2-one via 2-amino-2-methylhexanenitrile.

FIG. 14 shows the preparation of the compound of Formula VIb via stepsof nucleophilic addition, Bz protection, reduction, anddeprotection/TsOH salt formation.

FIG. 15 shows the preparation of the compound of Formula VIb via stepsof reduction of a salt of (R)-2-amino-2-methylhexanoic acid and TsOHsalt formation.

FIG. 16 shows the preparation of (R)-2-amino-2-methylhexanoic acidhydrochloride from (2S,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-onevia steps of alkylation and hydrolysis.

DETAILED DESCRIPTION OF THE DISCLOSURE I. General

The present disclosure provides methods for preparing compounds ofFormula I or a salt thereof, in particular(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol.The present disclosure also provides methods for preparing compounds ofFormula III, IV, V, VI, VII, VIII, IX, and X. In addition, the presentdisclosure provides compounds of Formula III, IV, V, and XI.

II. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

“Alkyl” refers to a straight or branched, saturated, aliphatic radicalhaving the number of carbon atoms indicated (i.e., C₁₋₆ means one to sixcarbons). Alkyl can include any number of carbons, such as C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈, C₁₋₉, C₁₋₁₀, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄,C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ and C₅₋₆. For example, C₁₋₆ alkyl includes, butis not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, etc.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. Alkoxy groups canhave any suitable number of carbon atoms, such as C₁-C₆. Alkoxy groupsinclude, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, butoxy,2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.

“Cycloalkyl” refers to a saturated or partially unsaturated, monocyclic,fused bicyclic or bridged polycyclic ring assembly containing from 3 to12 carbon ring atoms, or the number of atoms indicated. Cycloalkyl caninclude any number of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈,C₅₋₈, C₆₋₈, C₃₋₉, C₃₋₁₀, C₃₋₁₁, and C₃₋₁₂. Saturated monocycliccycloalkyl rings include, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic andpolycyclic cycloalkyl rings include, for example, norbornane,[2.2.2]bicyclooctane, decahydronaphthalene and adamantane. Cycloalkylgroups can also be partially unsaturated, having one or more double ortriple bonds in the ring. Representative cycloalkyl groups that arepartially unsaturated include, but are not limited to, cyclobutene,cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers),cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is asaturated monocyclic C₃-C₈ cycloalkyl, exemplary groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclicC₃₋₆ cycloalkyl, exemplary groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“N-linked heterocycloalkyl” or “nitrogen-linked heterocycloalkyl” refersto the heterocycloalkyl group linked via N-position on the ring. Forexample, N-linked aziridinyl is aziridin-1-yl, N-linked azetidinyl isazetidin-1-yl, N-linked pyrrolidinyl is pyrrolidin-1-yl, N-linkedpiperidinyl is piperidin-1-yl, N-linked pyrazolidinyl ispyrazolidin-1-yl or pyrazolidin-2-yl, N-linked imidazolidinyl can beimidazolidin-1-yl or imidazolidin-3-yl, N-linked piperazinyl ispiperazin-1-yl or piperazin-4-yl, N-linked oxazolidinyl isoxazolidin-3-yl, N-linked isoxazolidiny is isoxazolidin-2-yl, N-linkedthiazolidinyl is thiazolidin-3-yl, N-linked isothiazolidinyl isisothiazolidin-2-yl, and N-linked morpholinyl is 4-morpholinyl.

“OMs” refers to methanesulfonate; “OTs” refers to p-toluenesulfonate;and “OTf” refers to trifluoromethanesulfonate.

“Forming a reaction mixture” refers to the process of bringing intocontact at least two distinct species such that they mix together andcan react, either modifying one of the initial reactants or forming athird, distinct, species, a product. It should be appreciated, however,the resulting reaction product can be produced directly from a reactionbetween the added reagents or from an intermediate from one or more ofthe added reagents which can be produced in the reaction mixture.

“Acid” refers to a compound that is capable of donating a proton (H⁺)under the Bronsted-Lowry definition, or is an electron pair acceptorunder the Lewis definition. Acids useful in the present disclosure areBrønsted-Lowry acids that include, but are not limited to, alkanoicacids or carboxylic acids (formic acid, acetic acid, citric acid, lacticacid, oxalic acid, etc.), fluorinated carboxylic acids (trifluoroaceticacid), sulfonic acids and mineral acids, as defined herein. Mineralacids are inorganic acids such as hydrogen halides (hydrofluoric acid,hydrochloric acid, hydrobromic acid, etc.), halogen oxoacids(hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid,nitric acid, phosphoric acid, chromic acid and boric acid. Sulfonicacids include methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, triflouromethanesulfonic acid, among others.

“Lewis Acid” refers to a compound or ionic species which can accept anelectron pair from a donor compound. The Lewis acids useful in thepresent disclosure include, but are not limited to, boron trifluoridediethyl etherate, lithium chloride, zinc chloride, titaniumtetrachloride, silicon tetrachloride, aluminum chloride, samarium(II)iodide, cerium(III) chloride, and lanthanum(III) chloride lithiumchloride complex.

“Base” refers to a functional group that deprotonates water to produce ahydroxide ion. Bases useful in the present disclosure include organicbases and inorganic bases. Exemplary organic bases include amines,carboxylates, alkali alkoxides, metal amides, and alkyl or alkenylmetalcompounds, as defined herein. Exemplary inorganic bases include alkalibicarbonates, alkali carbonates, alkali phosphates tribasic, alkaliphosphate dibasic, alkali hydroxides, and alkali hydride, as definedherein. Amines useful in the present disclosure as bases includetertiary amines, aromatic amine bases, and amidine-based compounds, asdefined herein.

“Tertiary amine” refers to a compound having formula N(R)₃ wherein the Rgroups can be alkyl, aryl, heteroalkyl, heteroaryl, among others, or twoR groups together form a N-linked heterocycloalkyl. The R groups can bethe same or different. Non-limiting examples of tertiary amines includetriethylamine, tri-n-butylamine, N,N-diisopropylethylamine,N-methylpyrrolidine, N-methylmorpholine, dimethylaniline,diethylaniline, 1,8-bis(dimethylamino)naphthalene, quinuclidine, and1,4-diazabicylo[2.2.2]-octane (DABCO).

“Aromatic amine base” refers to a N-containing 5- to 10-memberedheteroaryl compound or a tertiary amine having formula N(R)₃ wherein atleast one R group is an aryl or heteroaryl. Aromatic amine bases usefulin the present application include, but are not limited to, pyridine,lutidines (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine),collidines (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine,2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine),4-dimethylaminopyridine, imidazole, dimethylaniline, and diethylaniline.

“Amidine-based compounds” herein refers to a class of chemical compoundsthat include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) and 1,5-diazabicyclo[4.3.0]non-5-en (DBN).

“Carboxylates” refers to a class of chemical compounds which arecomposed of an alkali metal cation or a phosphonium and the carboxylateanion (RC(O)O) where the R group can be alkyl or aryl. Carboxylatesuseful in the present disclosure include, but are not limited to,lithium acetate (LiOC(O)CH₃), sodium acetate (NaOC(O)CH₃), potassiumacetate (KOC(O)CH₃), cesium acetate (CsOC(O)CH₃), potassiumtrimethylacetate (KOC(O)C(CH₃)₃), and tetrabutylphosphonium malonate.

“Alkali bicarbonate” refers to a class of chemical compounds which arecomposed of an alkali metal cation and the hydrogencarbonate anion (HCO₃⁻). Alkali carbonates useful in the present disclosure include lithiumbicarbonate (LiHCO₃), sodium bicarbonate (NaHCO₃), potassium bicarbonate(KHCO₃), and cesium bicarbonate (CsHCO₃).

“Alkali carbonate” refers to a class of chemical compounds which arecomposed of an alkali metal cation and the carbonate anion (CO₃ ²⁻).Alkali carbonates useful in the present disclosure include lithiumcarbonate (Li₂CO₃), sodium carbonate (Na₂CO₃), potassium carbonate(K₂CO₃), and cesium carbonate (Cs₂CO₃).

“Alkali phosphate tribasic” refers to a class of chemical compoundswhich are composed of an alkali metal cation and the phosphate anion(PO₄ ³⁻). Alkali phosphates tribasic useful in the present disclosureinclude sodium phosphate tribasic (Na₃PO₄) and potassium phosphatetribasic (K₃PO₄).

“Alkali phosphate dibasic” refers to a class of chemical compounds whichare composed of an alkali metal cation and the hydrogenphosphate anion(HPO₄ ²⁻). Alkali phosphates dibasic useful in the present disclosureinclude sodium phosphate dibasic (Na₂HPO₄) and potassium phosphatedibasic (K₂HPO₄).

“Alkali hydroxide” refers to a class of chemical compounds which arecomposed of an alkali metal cation and the hydroxide anion (OH⁻). Alkalihydroxides useful in the present disclosure include lithium hydroxide(LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), and cesiumhydroxide (CsOH).

“Alkali alkoxide” refers to a class of chemical compounds which arecomposed of an alkali metal cation and the alkoxide anion (RO⁻), whereinR is C₁₋₄ alkyl. Alkali alkoxides useful in the present disclosureinclude, but are not limited to, sodium isopropoxide, sodium methoxide,sodium tert-butoxide, potassium tert-butoxide, and potassiumisopropoxide.

“Metal amide” refers to a class of coordination compounds composed of ametal center with amide ligands of the form —NR₂, wherein R is alkyl,cycloalkyl, or silyl. Metal amides useful in the present disclosureinclude, but are not limited to, lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)-amide, lithium2,2,6,6,-tetramethylpiperidide, 2,2,6,6-tetramethylpiperidinylmagnesiumchloride, bis(2,2,6,6-tetramethylpiperidinyl)magnesium, anddi-n-butyllithium(2,2,6,6-tetramethylpiperidinyl)magnesate).

“Alkyl- and alkenylmetal compound” refers to a class of chemicalcompounds composed of a metal center bond to alkyl or alkenyl. Alkyl-and alkenylmetal compounds useful in the present disclosure include, butare not limited to, n-butyllithium, isopropylmagnesium chloride,tri-n-butyllithium magnesate, di-n-butylmagnesium,di-sec-butylmagnesium, and ethyl n-butylmagnesium.

“Alkali hydride” refers to a class of chemical compounds composed of analkali metal cation and the hydride anion (H⁻). Alkali hydrides usefulin the present disclosure include lithium hydride, sodium hydride andpotassium hydride.

“Protecting group” refers to a compound that renders a functional groupunreactive to a particular set of reaction conditions, but that is thenremovable in a later synthetic step so as to restore the functionalgroup to its original state. Such protecting groups are well known toone of ordinary skill in the art and include compounds that aredisclosed in “Protective Groups in Organic Synthesis”, 4th edition, T.W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 2006, which isincorporated herein by reference in its entirety.

“Amino protecting group” refers to a protecting group that is used toprotect an amino group. “Amino” as used herein, and unless otherwisespecified, refers to —NH₂. Exemplary amino protecting groups include,but are not limited to, a carbobenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group,9-fluorenylmethyloxycarbonyl (Fmoc) group, acetyl (Ac) group, benzoyl(Bz) group, benzyl (Bn) group, carbamate group, p-methoxybenzyl (PMB),3,4-dimethoxybenzyl (DMB), p-methoxyphenyl (PMP), Tosyl (Ts) group, Troc(trichloroethyl chloroformate) group, and other sulfonamides (Nosyl &Nps) groups.

“Deprotecting agent” refers to one or more chemicals or agents thatremove the protecting group as defined above so that the functionalgroup is restored to its original state.

“Metal” refers to elements of the periodic table that are metallic andthat can be neutral, or negatively or positively charged as a result ofhaving more or fewer electrons in the valence shell than is present forthe neutral metallic element. Metals useful in the present disclosureinclude the alkali metals and transition metals. Alkali metals in thepresent disclosure include alkali metal cations. Alkali metal cationsuseful in the present disclosure include Li⁺, Na⁺, K⁺, and Cs⁺.Transition metals useful in the present disclosure include Sc, Ti, V,Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La,Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg and Ac. Transition metals useful inthe present disclosure include transition metal cations, for example,Cd²⁺, Co²⁺, Co⁺, Cr²⁺, Cr⁺, Cu⁺ (i.e., Cu(I)), Cu²⁺ (i.e., Cu(II)),Fe²⁺, Fe⁺, Mn²⁺, Mn⁺, Ni²⁺, Ni⁺, Pd²⁺ (i.e., Pd(II)), and Zn²⁺.

“Catalyst” refers to a substance that increases the rate of a chemicalreaction by reducing the activation energy, but which is left unchangedby the reaction. Catalysts may be classified as either homogeneous orheterogeneous. A homogeneous catalyst is one whose molecules aredispersed in the same phase as the reactant molecules. A heterogeneouscatalyst is one whose molecules are not in the same phase as thereactants, which are typically gases or liquids that are adsorbed ontothe surface of the solid catalyst. Catalysts useful in the presentdisclosure are both homogeneous catalysts and heterogeneous catalysts.

“Transition-metal catalyst” refers to a compound that is composed of atransition metal as defined above that can be neutral or positivelycharged.

“Ligand” refers to a molecule (functional group) that binds to a centralmetal atom to form a coordination complex. The bonding with the metalgenerally involves formal donation of one or more of the ligand'selectron pairs. The nature of metal-ligand bonding can range fromcovalent to ionic. Furthermore, the metal-ligand bond order can rangefrom one to three. In general, ligands are viewed as electron donors andthe metals as electron acceptors. Exemplary ligands in the presentdisclosure are tertiary amines as defined above, polypyridyl ligands asdefined herein, and amino acids as defined herein.

“Polypyridyl ligand” refers to a class of compounds containing at leasttwo pyridine moieties, which are either connected by a bond (e.g.,2,2′-bipyridine compounds) or a part of a fused tricyclic aromatic ringassembly containing 14 ring atoms (e.g., 1,10-phenanthroline compounds).Exemplary polypyridyl ligands include, but are not limited to,2,2′-bipyridine, 1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine,6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine, and2,2′-bipyridine-4,4′-dicarboxylic acid.

“Amino acid” refers to naturally occurring and synthetic amino acids, aswell as amino acid analogs that function in a manner similar to thenaturally occurring amino acids. Naturally occurring amino acids arethose encoded by the genetic code, as well as those amino acids that arelater modified, e.g., hydroxyproline, γ-carboxyglutamate, andO-phosphoserine.

“Phase-transfer agent” or “phase-transfer catalyst (PTC)” refers to acatalyst that facilitates the migration of a reactant from one phaseinto another phase where reaction occurs. Phase-transfer catalysis is aspecial form of heterogeneous catalysis. Ionic reactants are oftensoluble in an aqueous phase but insoluble in an organic phase in theabsence of the phase-transfer catalyst. The catalyst functions like adetergent for solubilizing the salts into the organic phase. By using aPTC process, one can achieve faster reactions, obtain higher conversionsor yields, make fewer byproducts, eliminate the need for expensive ordangerous solvents that will dissolve all the reactants in one phase,eliminate the need for expensive raw materials and/or minimize wasteproblems. PTC is not limited to systems with hydrophilic and hydrophobicreactants. PTC is sometimes employed in liquid/solid and liquid/gasreactions. As the name implies, one or more of the reactants aretransported into a second phase which contains both reactants.Phase-transfer catalysts for anionic reactants are often quaternaryammonium salts, as defined herein.

“Quaternary ammonium salt” refers to a salt of a quaternary ammoniumcation, as defined herein. Quaternary ammonium cation, also known asquat, refers to a positively charged compound having the formula NR₄ ⁺where R groups can be alkyl, aryl, or a combination thereof. Unlike theammonium ion (NH₄ ⁺) and the primary, secondary, or tertiary ammoniumcations, the quaternary ammonium cations are permanently charged,independent of the pH of their solution.

“Activating agent” refers to a reagent capable of converting a lessreactive functional group to a more reactive functional group in themolecule, which has an increased propensity to undergo a specifiedchemical reaction. In some embodiments, for example, the activatingagents convert the —OH group in the compound of Formula V to a reactivefunction group (e.g., —Cl, —OMs, —OTs, or —OTf). In some embodiments,the activating agents are peptide coupling agents known in the art thatactivate the —C(O)OH group (e.g., the compound of Formula VIII) and thenreact with an amine to form an amide (e.g., the compound of Formula V).Additional non-limiting examples of a reactive function group includeOSO₃H and —OSO₃—.

“Chlorinating agent” refers to a reagent capable of adding a chlorogroup, —Cl, to a compound. Representative chlorinating agents include,but are not limited to, phosphorous oxychloride, thionyl chloride,oxalyl chloride and sulfuryl chloride.

“Brominating agent” refers to a reagent capable of adding a bromo group,—Br, to a compound. Representative brominating agents include, but arenot limited to, bromine, N-bromosuccinimide, triphenylphosphinedibromide, tetrabutylammonium tribromide, trimethylphenylammoniumtribromide, N-bromoacetamide, pyridinium tribromide,dibromodimethylhydantoin, tribromoisocyanuric acid, N-bromosaccharin,and 1,2-dibromo-1,1,2,2-tetrachloroethane.

“Sulfonating agent” refers to a reagent capable of adding a sulfonategroup, —OSO₃ ⁻, to a compound. Representative sulfonating agentsinclude, but are not limited to, sulfur trioxide, sulfur trioxidecomplexes (e.g., dioxane, pyridine, polyvinylpyridine, trimethylamine,triethylamine, dimethylaniline, thioxane, bis(2-chloroethyl)ether,2-methylpyridine, quinoline, N,N′-dimethylformamide, tri-n-propylamine,tri-n-butylamine, N-alkylmorpholines (methyl, ethyl, n-butyl),pentamethylguanidine, 4′-methylacetanilide,N,N′-diethyl-4-toluenesulfonamide, tetramethylurea,tetramethyladipamide, N,N′-dimethylurethane, formylmorpholide,N,N′-dimethylbenzamide, dimethylcyanamide, n-propylpiperidine,n-isoamylpiperidine, N-benzylpiperidine, trimethylphosphine oxide,tetrahydrofuran, diethylsulfide, anthraquinone, benzanthrone,benzonapthone, or 2,6-dimethyl-γ-pyrone), chlorosulfonic acid, andsulfur dioxide.

“Promoter” refers to a substance added to a reactant (e.g., achlorinating agent as defined above) to improve its performance in achemical reaction (e.g., a formation of acyl chloride of Formula VIIfrom an acid of Formula VIII). By itself the promoter has little or nocatalytic effect in the reaction.

“Cyclization agent” or “cyclization agents” refer to one or morereagents (when used in a combination) capable of promoting a cyclizationreaction (e.g., the 4,5-dihydrooxazole formation from the compound ofFormula V) via reactions known in the art.

“Solvent” refers to a substance, such as a liquid, capable of dissolvinga solute. Solvents can be polar or non-polar, protic or aprotic. Polarsolvents typically have a dielectric constant greater than about 5 or adipole moment above about 1.0, and non-polar solvents have a dielectricconstant below about 5 or a dipole moment below about 1.0. Proticsolvents are characterized by having a proton available for removal,such as by having a hydroxy or carboxy group. Aprotic solvents lack sucha group. Representative polar protic solvents include alcohols(methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid,acetic acid, etc.) and water. Representative polar aprotic solventsinclude dichloromethane, chloroform, tetrahydrofuran,methyltetrahydrofuran, diethyl ether, 1,4-dioxane, acetone, ethylacetate, dimethylformamide, acetonitrile and dimethyl sulfoxide.Representative non-polar solvents include alkanes (pentanes, hexanes,etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, andtoluene. Other solvents are useful in the present disclosure.

Solvents can also be grouped based on their chemical structures, forexample, ethers (e.g., diethyl ether, methyl tert-butyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), ketones(e.g., acetone, methyl isobutyl ketone, etc.), esters (ethyl acetate,butyl acetate, isobutyl acetate, etc.), aromatic solvents (e.g.,benzene, toluene, xylenes, etc.), chlorinated solvents (e.g.,dichloromethane, 1,2-dichloroethane, etc.), hydrocarbons (n-heptane,hexanes, cyclohexane, methylcyclohexane, etc.), alcohols (methanol,ethanol, propanol, isopropanol, etc.), or acids (e.g., formic acid,acetic acid, etc.).

“Salt” refers to acid or base salts of the compounds used in the methodsof the present disclosure. Salts useful in the present disclosureinclude, but are not limited to, hemisulfate, sulfate, chloride,bromide, carbonate, nitrate, and acetate salts. A hemisulfate saltrefers a compound in which only one of two basic groups is formed a saltwith sulfuric acid. A carbonate salt includes a hydrogencarbonate (orbicarbonate) salt. Illustrative examples of pharmaceutically acceptablesalts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoricacid, and the like) salts, organic acid (acetic acid, propionic acid,glutamic acid, citric acid and the like) salts, quaternary ammonium(methyl iodide, ethyl iodide, and the like) salts. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., 1985, which is incorporated herein by reference.

III. Methods of Preparing Compounds

The present disclosure includes several methods of preparing thecompounds of Formula I.

A. Method of Preparing Compounds of Formula I from Formula III

1. Preparation of Formula I from Formula III

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula III:

-   -   -   or a salt thereof, a compound having the Formula            PG-NHC(═NH)NH₂ or a salt thereof, a first base, and a first            solvent to form a compound of Formula II

-   -   -   or a salt thereof; and

    -   b) forming a second reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        second solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ can each independently be hydrogen, F,        Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogen or        methyl; R⁵ can be C₃₋₆ alkyl; X can be F, Cl, Br, I, or OTs; and        PG can be an amino protecting group.

In one embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula III:

-   -   -   or a salt thereof, a compound having the formula            PG-NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent to form a            compound of Formula II:

-   -   -   or a salt thereof; and

    -   b) forming a second reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        second solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ can each independently be hydrogen, F,        Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogen or        methyl; R⁵ can be C₃₋₆ alkyl; X can be F, Cl, Br, I, or OTs; and        PG can be an amino protecting group.

In one embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula III:

-   -   -   or a salt thereof, a compound having the formula            PG-NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent to form a            compound of Formula II:

-   -   -   or a salt thereof; and

    -   b) forming a second reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        second solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ can each independently be hydrogen, F,        Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogen or        methyl; R⁵ can be C₃₋₆ alkyl; X can be Cl, Br, I, or OTs; and PG        can be an amino protecting group.

The compound having the formula PG-NHC(═NH)NH₂ can be in any suitableform. In some embodiments, the compound having the formulaPG-NHC(═NH)NH₂ can be in a neutral form. In some embodiments, thecompound having the formula PG-NHC(═NH)NH₂ can be in a salt form. Insome embodiments, the compound having the formula PG-NHC(═NH)NH₂ can bea hemisulfate, a sulfate, a chloride, a bromide, a carbonate, a nitrate,or an acetate salt thereof. In some embodiments, the compound having theformula PG-NHC(═NH)NH₂ can be of Formula IX:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula IX can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula IX can be a hemisulfate salt wherein n can be ½.

PG can be an amino protecting group. Suitable amino protecting groupsinclude, but are not limited to, a carbobenzyloxy (Cbz) group, ap-methoxybenzyl carbonyl (Moz or MeOZ) group, a tert-Butyloxycarbonyl(BOC) group, a 2-trimethylsilylethyoxymethyl (SEM) group, a9-fluorenylmethyloxycarbonyl (Fmoc) group, an acetyl (Ac) group, abenzoyl (Bz) group, a benzyl (Bn) group, a carbamate group, ap-methoxybenzyl (PMB) group, a 2,4-dimethoxybenzyl group (DMB), a1-(2,4-dimethoxyphenyl)ethyl, a 3,4-dimethoxybenzyl (DMPB) group, ap-methoxyphenyl (PMP) group, a tosyl (Ts) group, a Troc (trichloroethylchloroformate) group, and other sulfonamides (Nosyl & Nps) groups. Insome embodiments, PG can be 2,4-dimethoxybenzyl.

In some embodiments, the compound of Formula IX can be of Formula IXa:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula IXa can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula IXa can be a hemisulfate salt having

The first transition-metal catalyst can be a compound that includes oneor more transition metals or transition metal cations. Suitabletransition metals include, but are not limited to, Sc, Ti, V, Cr, Mn,Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta,W, Re, Os, Ir, Pt, Au, Hg and Ac. Suitable transition metal cationsinclude, but are not limited to, Cd²⁺, Co²⁺, Co⁺, Cr²⁺, Cr⁺, Cu⁺ (i.e.,Cu(I)), Cu²⁺ (i.e., Cu(II)), Fe²⁺, Fe⁺, Mn²⁺, Mn⁺, Ni²⁺, Ni⁺, Pd²⁺(i.e., Pd(II)) and Zn²⁺. In some embodiments, the first transition-metalcatalyst includes a copper metal, a copper oxide, a copper (I) salt, acopper (II) salt, or combinations thereof. In some embodiments, thefirst transition-metal catalyst includes a copper (I) salt. In someembodiments, the first transition-metal catalyst includes a copper (II)salt. In some embodiments, the first transition-metal catalyst can beCu(I) iodide, Cu(I) bromide, Cu(I) chloride, Cu(I) acetate, Cu(I)carbonate, Cu(I) nitrate, Cu(I) sulfate, Cu(I) phosphate, Cu(I)3-methylsalicylate, Cu(I) thiophene-2-carboxylate, Cu(I) oxide, Cu(II)iodide, Cu(II) bromide, Cu(II) chloride, Cu(II) acetate, Cu(II)carbonate, Cu(II) nitrate, Cu(II) sulfate, Cu(II) pyrophosphate, Cu(II)phosphate, Cu(II) tartrate, Cu(II) oxide, or combinations thereof. Insome embodiments, the first transition-metal catalyst can be Cu(II)iodide, Cu(II) bromide, Cu(II) chloride, Cu(II) acetate, Cu(II)carbonate, Cu(II) nitrate, Cu(II) sulfate, Cu(II) pyrophosphate, Cu(II)phosphate, Cu(II) tartrate, Cu(II) oxide, or combinations thereof. Insome embodiments, the first transition-metal catalyst includes Cu(II)acetate. In some embodiments, the first transition-metal catalyst can beCu(II) acetate.

The first base can be an alkali carbonate, an alkali bicarbonate, analkali phosphate tribasic, a carboxylate, an amidine-based compound, orcombinations thereof. Suitable alkali carbonates include lithiumcarbonate, sodium carbonate, potassium carbonate, and cesium carbonate.Suitable alkali bicarbonates include lithium bicarbonate, sodiumbicarbonate, and potassium bicarbonate. Suitable alkali phosphatestribasic include sodium phosphate tribasic and potassium phosphatetribasic. Suitable carboxylates include, but are not limited to, lithiumacetate, sodium acetate, potassium acetate, cesium acetate, potassiumtrimethylacetate, and tetrabutylphosphonium malonate. Suitableamidine-based compounds include, but are not limited to,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-en (DBN). In some embodiments, the firstbase can be lithium carbonate, sodium carbonate, potassium carbonate,cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassiumbicarbonate, sodium phosphate tribasic, potassium phosphate tribasic,potassium acetate, potassium trimethylacetate, tetrabutylphosphoniummalonate, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-en, or combinations thereof. In someembodiments, the first base includes potassium phosphate tribasic. Insome embodiments, the first base can be potassium phosphate tribasic.

The first solvent can be any suitable polar or non-polar, protic oraprotic solvent. In some embodiments, the first solvent can beacetonitrile, propionitrile, N,N-dimethylacetamide,N-methyl-2-pyrrolidinone, dimethylsulfoxide, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether,isopropanol, 2-methylbutan-2-ol, ethyl acetate, isopropyl acetate,methyl isobutyl ketone, toluene, trifluorotoluene, xylenes, orcombinations thereof. In some embodiments, the first solvent includes2-methyltetrahydrofuran. In some embodiments, the first solvent includesacetonitrile. In some embodiments, the first solvent includes2-methyltetrahydrofuran and acetonitrile. In some embodiments, the firstsolvent can be 2-methyltetrahydrofuran and acetonitrile.

In some embodiments, the first reaction mixture further includes a firstligand. In some embodiments, the first ligand can be an amino acid, apolypyridyl ligand, or a tertiary amine. Suitable amino acids includenaturally occurring and synthetic amino acids, as well as amino acidanalogs that function in a manner similar to the naturally occurringamino acids. Suitable polypyridyl ligands include, but are not limitedto, 2,2′-bipyridine, 1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine,6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine,2,2′-bipyridine-4,4′-dicarboxylic acid and 2,2′:6′2″-terpyridine.Suitable tertiary amines include, but are not limited to, triethylamine,tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine,N-methylmorpholine, 1,4-diazabicylo[2.2.2]-octane, andN,N,N′,N′-tetramethylethylenediamine. In some embodiments, the firstligand can be arginine, histidine, lysine, aspartic acid, glutamic acid,serine, threonine, asparagine, glutamine, cysteine, selenocysteine,glycine, proline, alanine, valine, isoleucine, leucine, methionine,phenylalanine, tyrosine, tryptophan, α-(methylamino)isobutyric acid,(4-methyl-1-piperazinyl)acetic acid, N-acetyl-cysteine, 2,2′-bipyridine,1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine,6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine,2,2′-bipyridine-4,4′-dicarboxylic acid,N,N,N′,N′-tetramethylethylenediamine, or combinations thereof. In someembodiments, the first ligand includes cysteine, selenocysteine,N-acetyl-cysteine, or homocysteine. In some embodiments, the firstligand includes cysteine. In some embodiments, the first ligand includesL-cysteine. In some embodiments, the first ligand can be cysteine,selenocysteine, N-acetyl-cysteine, or homocysteine. In some embodiments,the first ligand can be cysteine. In some embodiments, the first ligandcan be L-cysteine.

In general, the first reaction (i.e., step a)) can be performed at anambient to an elevated temperature. For example, the first reactionmixture can be at a temperature of from 30° C. to 110° C. or heated toreflux. In some embodiments, the first reaction mixture can be at atemperature of from 40° C. to 100° C., from 50° C. to 100° C., from 50°C. to 90° C., from 60° C. to 90° C., from 70° C. to 90° C., or about 80°C. In some embodiments, the first reaction mixture can be at atemperature of from 55° C. to a reflux temperature. In some embodiments,the first reaction mixture can be heated to reflux.

Once the first reaction is complete, the first transition metal catalystcan be removed from the reaction mixture by a second ligand, forexample, ethylenediaminetetraacetic acid (EDTA) or EDTA disodium salt.In some embodiments, upon completion of the first reaction, the firsttransition metal catalyst can be removed from the first reaction mixtureusing a second ligand. In some embodiments, the second ligand includesethylenediaminetetraacetic acid or a salt thereof. In some embodiments,upon completion of the first reaction, the first transition metalcatalyst can be removed from the first reaction mixture usingethylenediaminetetraacetic acid or a salt thereof. In some embodiments,upon completion of the first reaction, Cu(II) can be removed from thefirst reaction mixture using ethylenediaminetetraacetic acid disodiumsalt.

The compound of Formula II can be deprotected by various methods knownin the art to provide the compound of Formula I or a salt thereof. WhenPG is 2,4-dimethoxybenzyl, the compound of Formula II can be deprotectedby various methods, for example, under acidic, reductive(hydrogenolysis), or oxidative conditions to provide the compound ofFormula I or the salt thereof.

In some embodiments, the deprotecting agent can be an acid. In someembodiments, the acid can be trifluoroacetic acid, trichloroacetic acid,acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoricacid, or combinations thereof. In some embodiments, the acid includestrifluoroacetic acid. In some embodiments, the acid can betrifluoroacetic acid.

In some embodiments, the deprotecting agent can be a hydrogen source andthe second reaction mixture further includes a second transition-metalcatalyst. In some embodiments, the hydrogen source can be ammoniumformate, formic acid, hydrogen gas, or combinations thereof. In someembodiments, the hydrogen source includes hydrogen gas. In someembodiments, the hydrogen source includes ammonium formate. In someembodiments, the hydrogen source includes formic acid. In someembodiments, the second transition-metal catalyst can be palladiumhydroxide on carbon, palladium on carbon, or platinum oxide. In someembodiments, the second transition-metal catalyst includes palladiumhydroxide on carbon. In some embodiments, the second transition-metalcatalyst includes palladium on carbon. In some embodiments, the secondtransition-metal catalyst includes platinum oxide. In some embodiments,the deprotecting agent can be hydrogen gas and the second reactionmixture further includes palladium hydroxide on carbon, palladium oncarbon, or platinum oxide. In some embodiments, the deprotecting agentincludes ammonium formate and the second reaction mixture furtherincludes palladium hydroxide on carbon, palladium on carbon, or platinumoxide. In some embodiments, the deprotecting agent includes formic acidand the second reaction mixture further includes palladium hydroxide oncarbon, palladium on carbon, or platinum oxide. In some embodiments, thedeprotecting agent includes formic acid and the second solvent includesformic acid.

In some embodiments, the hydrogen source can be hydrogen gas. In someembodiments, the hydrogen source can be ammonium formate. In someembodiments, the hydrogen source can be formic acid. In someembodiments, the second transition-metal catalyst can be palladiumhydroxide on carbon. In some embodiments, the second transition-metalcatalyst can be palladium on carbon. In some embodiments, the secondtransition-metal catalyst can be platinum oxide. In some embodiments,the deprotecting agent can be ammonium formate and the second reactionmixture further includes palladium hydroxide on carbon, palladium oncarbon, or platinum oxide. In some embodiments, the deprotecting agentcan be formic acid and the second reaction mixture further includespalladium hydroxide on carbon, palladium on carbon, or platinum oxide.In some embodiments, the deprotecting agent can be formic acid and thesecond solvent can be formic acid.

In some embodiments, the deprotecting agent can be boron tribromide,2,3-dichloro-5,6-dicyano-1,4-benzoquinone, ceric ammonium nitrate, or acombination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

The second solvent can be any suitable polar or non-polar, protic oraprotic solvent. In some embodiments, the second solvent can be ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene,xylenes, trifluorotoluene, anisole, dimethylsulfoxide, propionitrile,butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene,methanol, ethanol, isopropanol, water, formic acid, acetic acid,trichloroacetic acid, or combinations thereof. In some embodiments, thesecond solvent includes formic acid. In some embodiments, the secondsolvent includes dichloromethane. In some embodiments, the secondsolvent can be formic acid. In some embodiments, the second solvent canbe dichloromethane.

In general, the second reaction (i.e., step b)) can be performed at anysuitable temperature, for example, at a temperature of from −10° C. to80° C. In some embodiments, the second reaction mixture can be at atemperature of from −10° C. to 80° C., from 0° C. to 50° C., from 10° C.to 50° C., from 20° C. to 50° C., or from 20° C. to 40° C. In someembodiments, the second reaction mixture can be at a temperature of from20° C. to 40° C. In some embodiments, the second reaction mixture can beat a temperature of about 30° C. In some embodiments, the secondreaction mixture can be at a temperature of about 40° C. In someembodiments, the second solvent includes dichloromethane, and the secondreaction mixture can be heated to reflux. In some embodiments, thesecond solvent can be dichloromethane, and the second reaction mixturecan be heated to reflux. 2. Preparation of Formula III from Formula IV

In some embodiments, the method further includes prior to step a):

-   -   a1) forming a third reaction mixture including a compound of        Formula IV:

-   -   -   or a salt thereof, a second base, and a third solvent to            form the compound of Formula III, or the salt thereof,            wherein AG¹ is Cl, Br, OSO₃H, OSO₃ ⁻, OMs, OTs, or OTf.

In some embodiments, the method further includes prior to step a):

-   -   a1) forming a third reaction mixture including a compound of        Formula IV:

-   -   -   or a salt thereof, a second base, and a third solvent to            form the compound of Formula III, or the salt thereof,            wherein AG¹ is Cl, Br, OMs, OTs, or OTf.

The second base can be a tertiary amine, an aromatic amine base, analkali carbonate, an alkali bicarbonate, an alkali phosphate tribasic,an alkali hydroxide, or combinations thereof. Suitable tertiary aminesinclude, but are not limited to, triethylamine, tri-n-butylamine,N,N-diisopropylethylamine, N-methylpyrrolidine, and N-methylmorpholine.Suitable aromatic amine bases include, but are not limited to, pyridine,lutidines (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine),collidines (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine,2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), and4-dimethylaminopyridine. Suitable alkali carbonates include lithiumcarbonate, sodium carbonate, potassium carbonate, and cesium carbonate.Suitable alkali bicarbonates include lithium bicarbonate, sodiumbicarbonate, and potassium bicarbonate. Suitable alkali phosphatestribasic include sodium phosphate tribasic and potassium phosphatetribasic. Suitable alkali hydroxides includes lithium hydroxide, sodiumhydroxide, potassium hydroxide, and cesium hydroxide. In someembodiments, the second base can be triethylamine, tri-n-butylamine,N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine,pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium bicarbonate,potassium bicarbonate, potassium phosphate tribasic, sodium hydroxide,potassium hydroxide, or combinations thereof. The second base can be inan aqueous solution. In some embodiments, the second base includes anaqueous solution of sodium hydroxide. In some embodiments, the secondbase can be an aqueous solution of sodium hydroxide.

The third solvent can be any suitable polar aprotic solvent or non-polarsolvent. In some embodiments, the third solvent can be tetrahydrofuran,2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane,dichloromethane, 1,2-dichloroethane, benzene, toluene, xylenes, orcombinations thereof. In some embodiments, the third solvent includes2-methyltetrahydrofuran. In some embodiments, the third solvent can be2-methyltetrahydrofuran.

The third reaction (i.e., step a1)) can be performed with or without aphase-transfer agent. In some embodiments, the third reaction mixturefurther includes a phase-transfer agent. In some embodiments, thephase-transfer agent can be a quaternary ammonium salt. In someembodiments, the quaternary ammonium salt can be tetra-n-butylammoniumhydrogensulfate, tetra-n-butylammonium bromide, tetra-n-butylammoniumchloride, benzyltributylammonium bromide, benzyltriethylammoniumchloride, benzalkonium chloride, or dodecylethyldimethylammoniumbromide. In some embodiments, the quaternary ammonium salt includestetra-n-butylammonium hydrogensulfate. In some embodiments, thequaternary ammonium salt can be tetra-n-butylammonium hydrogensulfate.In some embodiments, the phase-transfer agent can betetra-n-butylammonium hydrogensulfate.

In general, the third reaction (i.e., step a1)) can be performed at anysuitable temperature. For example, the third reaction mixture can be ata temperature of from 0° C. to 80° C. In some embodiments, the thirdreaction mixture can be at a temperature of from 0° C. to 80° C., from10° C. to 60° C., from 10° C. to 50° C., from 15° C. to 50° C., from 20°C. to 50° C., or about 35° C. In some embodiments, the third reactionmixture can be at a temperature of from 15° C. to 50° C. In someembodiments, the third reaction mixture can be at a temperature of about35° C.

In some embodiments, the compound of Formula IV has the formula:

In some embodiments, the compound of Formula IV has the formula:

wherein Y⁺ is a metal ion M⁺, or ammonium salt HA⁺. Any suitable metalion M⁺ can be used, including, but not limited to, lithium, sodium,potassium, calcium, or cesium. Any suitable ammonium salt HA⁺ can beused, including, but not limited to trimethylammonium, triethylammonium,or dicyclohexylammonium. In some embodiments, Y^(m) is sodium. In someembodiments, Y⁺ is HNMe₃ ⁺. In some embodiments, the compound of FormulaIV has the formula:

In some embodiments, the third solvent includes acetonitrile,propionitrile, butyronitrile, N,N-dimethylacetamide,N-methyl-2-pyrrolidinone, dimethylsulfoxide, 2-methyltetrahydrofuran,tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, toluene,trifluorotoluene, xylenes, benzonitrile, dichloromethane,1,2-dichloroethane, chlorobenzene, methanol, ethanol, n-butanol,1-hexanol, 2-propanol, 2-methyl-2-butanol. In some embodiments, thethird solvent includes 2-methyl-2-butanol. In some embodiments, thethird solvent can be 2-methyl-2-butanol.

In some embodiments, the third reaction mixture further includes anadditive. Suitable additives include, but are not limited to, thionylchloride, oxalyl chloride, phosphorus(V) oxychloride, phosphorus(V)pentachloride, methanesulfonyl chloride, para-toluenesulfonic acid,methanesulfonic anhydride, trifluoromethanesulfonic anhydride, water,acetic anhydride, 4-dimethylamino pyridine, or a tetra-butylammoniumsalt (e.g., hydrogen sulfate, chloride, bromide, or iodide salt). Insome embodiments, the additive is absent.

3. Preparation of Formula IV from Formula V

In some embodiments, the method further includes prior to step a1):

-   -   a2) forming a fourth reaction mixture including a compound of        Formula V:

-   -   -   or a salt thereof, a first activating agent, and a fourth            solvent to form the compound of Formula IV:

-   -   -   or the salt thereof.

In some embodiments, AG¹ can be Cl; and the first activating agent canbe a first chlorinating agent. The first chlorinating agent can be anysuitable chlorinating agent capable of converting the —OH group ofFormula V to a corresponding —Cl group (i.e., AG¹ can be Cl in FormulaIV). In some embodiments, the first chlorinating agent can be oxalylchloride, thionyl chloride, phosphorus oxychloride, phosphoruspentachloride, or chlorosulfonic acid. In some embodiments, the firstchlorinating agent includes oxalyl chloride. In some embodiments, thefirst chlorinating agent includes thionyl chloride. In some embodiments,the first chlorinating agent can be oxalyl chloride. In someembodiments, the first chlorinating agent is thionyl chloride.

In some embodiments, AG¹ can be Br; and the first activating agent canbe a brominating agent. The brominating agent can be any suitablebrominating agent capable of converting the —OH group of Formula V to acorresponding —Br group (i.e., AG¹ can be Br in Formula IV). In someembodiments, the brominating agent can be triphenylphosphine dibromideortribromoisocyanuric acid.

In some embodiments, AG¹ can be OMs, OTs, or OTf; and the firstactivating agent can be methanesulfonyl chloride, methanesulfonicanhydride, para-toluenesulfonyl chloride, para-toluenesulfonic acid,para-toluenesulfonic anhydride, or trifluoromethanesulfonic anhydride.In some embodiments, AG¹ can be OMs; and the first activating agent canbe methanesulfonyl chloride or methanesulfonic anhydride. In someembodiments, AG¹ can be OMs; and the first activating agent includesmethanesulfonyl chloride. In some embodiments, AG¹ can be OTs; and thefirst activating agent includes para-toluenesulfonyl chloride. In someembodiments, AG¹ can be OTf; and the first activating agent includestrifluoromethanesulfonic anhydride. In some embodiments, AG¹ can be OTs;and the first activating agent can be para-toluenesulfonyl chloride. Insome embodiments, AG¹ can be OTf; and the first activating agent can betrifluoromethanesulfonic anhydride.

The fourth solvent can be any suitable polar aprotic solvent and/ornon-polar solvents. In some embodiments, the fourth solvent can betetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether,1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene,xylenes, or combinations thereof. In some embodiments, the fourthsolvent includes 2-methyltetrahydrofuran. In some embodiments, thefourth solvent can be 2-methyltetrahydrofuran.

In general, when the first activating agent can be the firstchlorinating agent, the fourth reaction (i.e., step a2)) can beperformed at any suitable temperature. For example, the fourth reactionmixture can be at a temperature of from 0° C. to 80° C. In someembodiments, the fourth reaction mixture can be at a temperature of from0° C. to 80° C., from 10° C. to 80° C., from 20° C. to 70° C., from 30°C. to 60° C., from 40° C. to 60° C., from 15° C. to 50° C., or about 50°C. In some embodiments, the fourth reaction mixture can be at atemperature of from 15° C. to 50° C. In some embodiments, the fourthreaction mixture can be at a temperature of about 50° C.

In some embodiments, the method further includes prior to step a1):

-   -   a2) forming a fourth reaction mixture including a compound of        Formula V:

-   -   -   or a salt thereof, a first activating agent, and a fourth            solvent to form a compound of Formula IV-2:

and

-   -   -   treating the compound of Formula IV-2 or the salt thereof            with an ion-exchange reagent in the fourth solvent to form            the compound of Formula IV:

-   -   -   or the salt thereof, wherein AG¹ is OSO₃H or OSO₃ ⁻.

In some embodiments, AG¹ can be OSO₃H or OSO₃ ⁻; and the firstactivating agent can be a sulfonating agent. The sulfonating agent canbe any suitable sulfonating agent capable of converting the —OH group ofFormula V to a corresponding —OSO₃H or OSO₃ ⁻. In some embodiments, thesulfonating agent can be sulfur trioxide, chlorosulfonic acid, sulfurdioxide, or a sulfur trioxide complex. In some embodiments, the sulfurtrioxide complex can be sulfur trioxide complexed with dioxane,pyridine, polyvinylpyridine, trimethylamine, triethylamine,dimethylaniline, thioxane, bis(2-chloroethyl)ether, 2-methylpyridine,quinoline, N,N′-dimethylformamide, tri-n-propylamine, tri-n-butylamine,N-alkylmorpholines (methyl, ethyl, n-butyl), pentamethylguanidine,4′-methylacetanilide, N,N′-diethyl-4-toluenesulfonamide,tetramethylurea, tetramethyladipamide, N,N′-dimethylurethane,formylmorpholide, N,N′-dimethylbenzamide, dimethylcyanamide,n-propylpiperidine, n-isoamylpiperidine, N-benzylpiperidine,trimethylphosphine oxide, tetrahydrofuran, diethylsulfide,anthraquinone, benzanthrone, benzonapthone, or 2,6-dimethyl-γ-pyrone. Insome embodiments, the sulfonating agent includes a sulfur trioxidetrimethylamine complex. In some embodiments, the sulfonating agent canbe a sulfur trioxide trimethylamine complex.

In some embodiments of the compound of Formula IV-2, wherein Y⁺ ishydrogen, pyridinium, trimethylammonium, triethylammonium,methylpyridinium, quinolinium, tri-n-propylammonium,tri-n-butylammonium, a morpholinium optionally substituted with methyl,ethyl, or n-butyl, petamethylguanidinium,N,N′-dimethylethylenediammonium, dimethylcyanamide, orbenzylpiperidinium. In some embodiments of Formula IV-2, Y⁺ istrimethylammonium.

In some embodiments, the ion exchange reagent can be an ion exchangeresin (e.g., Ion exchanger I, II, III, IV, or V; Amberlite® IR-120,e.g., H⁺ form, Na⁺ form, IRA-67, IRA-402, IRA-410, 15; and Dowex®, e.g.,50 WX 4, 50W-XZ8, 1-X8); a mineral acid (e.g., hydrochloric acid, orhydrobromic acid); a carboxylate (e.g., disodium sebacate, sodiumhexanoate, sodium 2-ethylhexanoate, calcium 2-ethylhexanoate, orpotassium 2-ethylhexanoate); a hydroxide or an alkoxide (e.g., lithiumtert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide,potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide,potassium hydroxide, or cesium hydroxide); an amine (e.g.,dicyclohexylamine, or N-methylcyclohexylamine); or others (e.g., sodiumtetrafluoroborate, potassium phosphate dibasic, calcium sulfate, orferrocyanic acid). In some embodiments, the ion exchange reagentincludes sodium 2-ethylhexanoate. In some embodiments, the ion exchangereagent can be sodium 2-ethylhexanoate.

In some embodiments, the compound of Formula IV is in an acid formhaving the formula:

In some embodiments, the compound of Formula IV is in a salt form havingthe formula:

wherein Y⁺ is a metal ion M⁺, or ammonium salt HA⁺. Any suitable metalion M⁺ can be used, such as, but not limited to, lithium, sodium,potassium, calcium, or cesium. Any suitable ammonium salt HA⁺ can beused, such as, but not limited to, trimethylammonium, triethylammonium,or dicyclohexylammonium. In some embodiments, Y⁺ is sodium. In someembodiments, the compound of Formula IV has the formula:

In some embodiments, the fourth solvent can be any suitable polaraprotic solvent and/or non-polar solvents. In some embodiments, thefourth solvent can be acetonitrile, propionitrile, butyronitrile,N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide,2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, isopropyl acetate, ethyl acetate, butyl acetate, isobutylacetate, acetone, methyl isobutyl ketone, toluene, trifluorotoluene,xylenes, benzonitrile, dichloromethane, 1,2-dichloroethane,chlorobenzene, or combinations thereof. In some embodiments, the fourthsolvent includes acetonitrile, 2-methyltetrahydrofuran, or a combinationthereof. In some embodiments, the fourth solvent includes acetonitrileand 2-methyltetrahydrofuran. In some embodiments, the fourth solvent canbe acetonitrile, 2-methyltetrahydrofuran, or a combination thereof. Insome embodiments, the fourth solvent can be acetonitrile and2-methyltetrahydrofuran.

In general, the sulfonating and ion-exchange steps of the fourthreaction (i.e., step a2) can be performed at any suitable temperature.For example, the sulfonating reaction mixture can be at a temperature offrom 0° C. to 100° C. In some embodiments, the sulfonating reactionmixture can be at a temperature of from 20° C. to 100° C., from 30° C.to 100° C., from 40° C. to 100° C., from 40° C. to 100° C., from 50° C.to 100° C., from 60° C. to 100° C., from 60° C. to 90° C., or from 60°C. to 80° C. In some embodiments, the sulfonating reaction mixture canbe at a temperature of from 60° C. to 80° C. For example, theion-exchange reaction mixture can be at a temperature of from 0° C. to50° C. In some embodiments, the ion-exchange reaction mixture can be ata temperature of from 10° C. to 40° C., from 15° C. to 40° C., from 15°C. to 30° C., or about 20° C. In some embodiments, the ion-exchangereaction mixture can be at a temperature of about 20° C. 4. Preparationof Formula III from Formula V

In some embodiments, the method further includes prior to step a):

-   -   a1-2) forming a fifth reaction mixture including a compound of        Formula V:

-   -   -   or a salt thereof, one or more cyclizing agents, and a fifth            solvent to form the compound of Formula III or the salt            thereof.

The one or more cyclizing agents can be any suitable reagents capable offorming the 4,5-dihydrooxazole moiety from the compound of Formula V viacyclization. The one or more cyclizing agents can be a reagent incombination with triphenylphosphine, for example,2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)/triphenylphosphine,diethyl azodicarboxylate (DEAD)/triphenylphosphine, diisopropylazodicarboxylate (DIAD)/triphenylphosphine, or carbontetrabromide/triphenylphosphine. The one or more cyclizing agents can bea dehydrating reagent used alone, for example, methylN-(triethylammoniosulfonyl)-carbamate (also known as Burgess reagent).The one or more cyclizing agents can be diethylaminosulfur trifluoride(DAST) that mediates the cyclization to form the 4,5-dihydrooxazolemoiety. In some embodiments, the one or more cyclizing agents are acombination of 2,3-dichloro-5,6-dicyano-p-benzoquinone andtriphenylphosphine, a combination of diethyl azodicarboxylate andtriphenylphosphine, a combination of diisopropyl azodicarboxylate andtriphenylphosphine, a combination of carbon tetrabromide andtriphenylphosphine, methyl N-(triethylammoniosulfonyl)-carbamate, ordiethylaminosulfur trifluoride.

The fifth solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the fifth solvent can betetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether,1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene,xylenes, or combinations thereof. In some embodiments, the fifth solventincludes 2-methyltetrahydrofuran. In some embodiments, the fifth solventcan be 2-methyltetrahydrofuran.

5. Preparation of Formula V from Formula VII and Formula VI

In some embodiments, the method further includes prior to step a2) ora1-2):

-   -   a3) forming a sixth reaction mixture including a compound of        Formula VII:

-   -   -   or a salt thereof, a compound of Formula VI:

-   -   -   or a salt thereof, a third base, and a sixth solvent to form            the compound of Formula V or the salt thereof.

The compound of Formula VI can be in any suitable form. In someembodiments, the compound of Formula VI can be in a neutral form. Insome embodiments, the compound of Formula VI can be in a salt form. Insome embodiments, the compound of Formula VI can be a tosylate saltthereof.

The third base can be a tertiary amine, an aromatic amine base, analkali carbonate, an alkali bicarbonate, an alkali phosphate tribasic,an alkali hydroxide, or combinations thereof. Suitable tertiary aminesinclude, but are not limited to, triethylamine, tri-n-butylamine,N,N-diisopropylethylamine, N-methylpyrrolidine, and N-methylmorpholine.Suitable aromatic amine bases include, but are not limited to, pyridine,lutidines (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine),collidines (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine,2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), and4-dimethylaminopyridine. Suitable alkali carbonates include lithiumcarbonate, sodium carbonate, potassium carbonate, and cesium carbonate.Suitable alkali bicarbonates include lithium bicarbonate, sodiumbicarbonate, and potassium bicarbonate. Suitable alkali phosphatestribasic include sodium phosphate tribasic and potassium phosphatetribasic. Suitable alkali hydroxides include lithium hydroxide, sodiumhydroxide, potassium hydroxide, and cesium hydroxide. In someembodiments, the third base can be triethylamine, tri-n-butylamine,N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine,pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, sodiumcarbonate, potassium carbonate, cesium carbonate, sodium bicarbonate,potassium bicarbonate, potassium phosphate tribasic, sodium hydroxide,potassium hydroxide, or combinations thereof. In some embodiments, thethird base can be in an aqueous solution. In some embodiments, the thirdbase includes potassium carbonate. In some embodiments, the third baseincludes an aqueous solution of potassium carbonate. In someembodiments, the third base can be potassium carbonate. In someembodiments, the third base can be an aqueous solution of potassiumcarbonate.

The sixth solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the sixth solvent furtherincludes water. In those embodiments, the sixth reaction (i.e., stepa3)) can be a biphasic reaction. In some embodiments, the sixth solventcan be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butylether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene,toluene, xylenes, water, or combinations thereof. In some embodiments,the sixth solvent includes 2-methyltetrahydrofuran. In some embodiments,the sixth solvent includes 2-methyltetrahydrofuran and water. In someembodiments, the sixth solvent can be 2-methyltetrahydrofuran. In someembodiments, the sixth solvent can be 2-methyltetrahydrofuran and water.

In general, the sixth reaction (i.e., step a3)) can be performed at anysuitable temperature. For example, the fourth reaction mixture can be ata temperature of from 0° C. to 60° C. In some embodiments, the fourthreaction mixture can be at a temperature of from 0° C. to 60° C., from10° C. to 50° C., from 10° C. to 40° C., from 20° C. to 40° C., from 20°C. to 30° C., or about 20° C. In some embodiments, the third reactionmixture can be at a temperature of from 20° C. to 30° C. In someembodiments, the third reaction mixture can be at a temperature of about20° C.

6. Preparation of Formula VII from Formula VIII

In some embodiments, the method further includes prior to step a3):

-   -   a4) forming a seventh reaction mixture including a compound of        Formula VIII:

-   -   -   or a salt thereof, a second chlorinating agent, a promoter,            and a seventh solvent to form the compound of Formula VII or            the salt thereof.

The second chlorinating agent can be any suitable chlorinating agentcapable of converting the —C(O)OH group of Formula VIII to the —C(O)Clgroup of Formula VII. In some embodiments, the second chlorinating agentcan be oxalyl chloride, thionyl chloride, phosphorus oxychloride,phosphorus pentachloride, or (chloromethylene)dimethyliminium chloride.In some embodiments, the second chlorinating agent includes oxalylchloride. In some embodiments, the second chlorinating agent includesthionyl chloride. In some embodiments, the second chlorinating agent canbe oxalyl chloride. In some embodiments, the second chlorinating agentcan be thionyl chloride.

In some embodiments, the promoter can be N,N-dimethylformamide,N,N-dimethylacetamide, or dichloromethylene-dimethyliminium chloride. Insome embodiments, the promoter includes N,N-dimethylformamide. In someembodiments, the promoter can be N,N-dimethylformamide.

The seventh solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the seventh solvent can betetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether,1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene,xylenes, or combinations thereof. In some embodiments, the seventhsolvent includes 2-methyltetrahydrofuran. In some embodiments, theseventh solvent can be 2-methyltetrahydrofuran.

In general, the seventh reaction (i.e., step a4)) can be performed atany suitable temperature. For example, the seventh reaction mixture canbe at a temperature of from 0° C. to 60° C. In some embodiments, theseventh reaction mixture can be at a temperature of from 0° C. to 60°C., from 10° C. to 50° C., from 10° C. to 40° C., from 20° C. to 40° C.,from 20° C. to 30° C., or about 20° C. In some embodiments, the seventhreaction mixture can be at a temperature of from 20° C. to 30° C. Insome embodiments, the seventh reaction mixture can be at a temperatureof about 20° C.

7. Preparation of Formula V from Formula VIII and Formula VI

In some embodiments, the method further includes prior to step a2) ora1-2):

-   -   a3-1) forming an eighth reaction mixture including a compound of        Formula VIII:

-   -   -   or a salt thereof, a compound of Formula VI:

-   -   -   or a salt thereof, a second activating agent, a fourth base,            and an eighth solvent to form the compound of Formula V or            the salt thereof.

The compound of Formula VI can be in in any suitable form. In someembodiments, the compound of Formula VI can be in a neutral form. Insome embodiments, the compound of Formula VI can be in a salt form. Insome embodiments, the compound of Formula VI can be a tosylate saltthereof.

The second activating agent can be any peptide coupling reagent capableof activating an acid group (e.g., the acid group of Formula III),thereby reacting with an amine (e.g., the compound of Formula VI) toform an amide bond (e.g., the amide group of formula V). The peptidecoupling reagents include isobutyl chloroformate,1,1′-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC),diisopropylcarbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), hydroxybenzotriazole (HOBt), and1-hydroxy-7-azabenzotriazole (HOAt). In some embodiments, the secondactivating agent can be isobutyl chloroformate or1,1′-carbonyldiimidazole.

The fourth base can be a tertiary amine, an aromatic amine base, or acombination thereof. Suitable tertiary amines include, but are notlimited to, triethylamine, tri-n-butylamine, N,N-diisopropylethylamine,N-methylpyrrolidine, and N-methylmorpholine. Suitable aromatic aminebases include, but are not limited to, pyridine, lutidines (e.g.,2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidines (e.g.,2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine,2,4,6-collidine, and 3,4,5-collidine), and 4-dimethylaminopyridine. Insome embodiments, the fourth base can be triethylamine,tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine,N-methylmorpholine, pyridine, 2,6-lutidine, 2,4,6-collidine,4-dimethylaminopyridine, or combinations thereof. In some embodiments,the fourth base includes N,N-diisopropylethylamine. In some embodiments,the fourth base can be N,N-diisopropylethylamine.

The eighth solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the eighth solvent can beN,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,dimethyl sulfoxide, acetonitrile, ethyl acetate, tetrahydrofuran,2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane,dichloromethane, 1,2-dichloroethane, benzene, toluene, xylenes, orcombinations thereof. In some embodiments, the eighth solvent includesN,N-dimethylformamide. In some embodiments, the eighth solvent includes2-methyltetrahydrofuran. In some embodiments, the eighth solventincludes N,N-dimethylformamide and 2-methyltetrahydrofuran. In someembodiments, the eighth solvent can be N,N-dimethylformamide. In someembodiments, the eighth solvent can be 2-methyltetrahydrofuran. In someembodiments, the eighth solvent can be N,N-dimethylformamide and2-methyltetrahydrofuran.

The compound of Formula I in a neutral form can be generated bycontacting the salt of the compound of Formula I with a base. In someembodiments, the method further includes c) forming a ninth reactionmixture including the salt of the compound of Formula I, a fifth base,and a ninth solvent to provide the compound of Formula I in a neutralform.

The fifth base can be an alkali carbonate or alkali hydroxide. Suitablealkali carbonates include sodium carbonate and potassium carbonate.Suitable alkali hydroxides include sodium hydroxide and potassiumhydroxide. In some embodiments, the fifth base can be sodium hydroxideor potassium hydroxide. In some embodiments, the fifth base includessodium hydroxide. In some embodiments, the fifth base can be in anaqueous solution. In some embodiments, the fifth base includes anaqueous solution of sodium hydroxide. In some embodiments, the fifthbase can be sodium hydroxide. In some embodiments, the fifth base can bean aqueous solution of sodium hydroxide.

The ninth solvent can be any suitable alcohol solvent, ester solvent,and/or water. In some embodiments, the ninth solvent can be methanol,ethanol, isopropanol, ethyl acetate, isopropyl acetate, water, orcombinations thereof. In some embodiments, the ninth solvent includes i)ethanol and water or ii) ethyl acetate and water. In some embodiments,the ninth solvent includes ethanol and water. In some embodiments, theninth solvent includes ethyl acetate and water. In some embodiments, theninth solvent can be i) ethanol and water or ii) ethyl acetate andwater. In some embodiments, the ninth solvent can be ethanol and water.In some embodiments, the ninth solvent can be ethyl acetate and water.

When the ninth solvent includes an ester solvent (e.g., ethyl acetate orisopropyl acetate), upon completion of the reaction, the reactionmixture after partition can be further treated with an aqueous solutionof sodium bicarbonate.

In general, the ninth reaction (i.e., step c)) can be performed at anysuitable temperature. For example, the ninth reaction mixture can be ata temperature of from 0° C. to 60° C. In some embodiments, the ninthreaction mixture can be at a temperature of from 0° C. to 60° C., from10° C. to 60° C., from 10° C. to 50° C., or from 20° C. to 40° C. Insome embodiments, the ninth reaction mixture can be at a temperature offrom 20° C. to 40° C. In some embodiments, the ninth reaction mixturecan be at a temperature of about 20° C. In some embodiments, the ninthreaction mixture can be at a temperature of about 40° C.

8. Preparation of Formula II from Formula III

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula II:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula III:

-   -   -   or a salt thereof, a compound having the Formula            PG-NHC(═NH)NH₂ or a salt thereof, and a first solvent to            form the compound of Formula II:

-   -   -   or the salt thereof,            wherein R¹, R², and R³ can each independently be hydrogen,            F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be            hydrogen or methyl; R⁵ can be C₃₋₆ alkyl; X can be F; and PG            can be an amino protecting group.

The compound having the Formula PG-NHC(═NH)NH₂ can be in any suitableform. In some embodiments, the compound having the FormulaPG-NHC(═NH)NH₂ can be in a neutral form. In some embodiments, thecompound having the Formula PG-NHC(═NH)NH₂ can be in a salt form. Insome embodiments, the compound having the Formula PG-NHC(═NH)NH₂ can bea hemisulfate, a sulfate, a chloride, a bromide, a carbonate, a nitrate,or an acetate salt thereof. In some embodiments, the compound having theFormula PG-NHC(═NH)NH₂ can be of Formula IXc:

In some embodiments, PG can be an amino protecting group. Suitable aminoprotecting groups include, but are not limited to,tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxylcarbonyl,allyloxycarbonyl, acetyl, trifluoroacetyl,2,2,5,7,8-Pentamethyl-chromane-6-sulfonyl chloride,para-toluenesulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl,2,4-dimethoxybenzyl, 4-methoxybenzyl, or 2-chlorobenzyl. In someembodiments, PG can be 2,4-dimethoxybenzyl.

In some embodiments, the first reaction mixture further comprises afirst base. The first base can be a carbonate (e.g., cesium carbonate,lithium carbonate, sodium carbonate, potassium carbonate, rubidiumcarbonate, magnesium carbonate, calcium carbonate, strontium carbonate,barium carbonate, nickel carbonate, zinc carbonate, silver carbonate, orammonium carbonate), a metal oxide (e.g., magnesium oxide), a hydroxide(e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, cesiumhydroxide, barium hydroxide, ammonium hydroxide, ortetra-n-butylammonium hydroxide), an alkoxide (e.g., lithium phenoxide),a silanolate (e.g., potassium trimethylsilanolate, sodiumtrimethylsilanolate, lithium silanolate, or sodiumdimethylphenylsilanolate), a phosphate (e.g. potassium phosphatetribasic, calcium phosphate tribasic, magnesium phosphate tribasic,sodium phosphate tribasic, sodium phosphate dibasic, or potassiumphosphate dibasic), a hydride (e.g., sodium hydride or potassiumhydride), an amine (e.g., N,N-diisopropylethyl amine, triethylamine,N,N,N′,N′-tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane,1-azabicyclo[2.2.2]octane, 1,8-diaza[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene pyridine, 1,1,3,3-tetramethylguanidine,4-methylmorpholine, 2-tert-buty-1,1,3,3-tetramethylguanidine,1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine,1,8-bis(dimethylamino)naphthalene, orN,N,N′N′-tetramethyl-1,8-napthalenediamine), an amide (e.g., lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, lithium diisopropyl amide, sodium diisopropylamide, or lithium dicyclohexylamide), an alkylmetal (e.g.,n-butyllithium, tert-butyllithium, methyllithium, phenyllithium, lithiumnaphthalenide, or sodium naphthalenide), an alkoxide (e.g., magnesiumtert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodiumtert-pentoxide, or potassium tert-pentoxide), a phosphorane (e.g.,tert-butylimino-tri(pyrrolidino)phosphorene,2-tert-butylimino-tri(pyrrolidino)phosphorene, or2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphorene),or combinations thereof. In some embodiments, the first base includescesium carbonate. In some embodiments, the first base can be cesiumcarbonate.

The first solvent can be any suitable polar or non-polar, protic oraprotic solvent. The first solvent can be a polar aprotic solvent (e.g.,N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, sulfolane, acetonitrile, propionitrile,butyronitrile, nitromethane, or nitroethane), an ether (tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butylether, or cyclopentyl methyl ether), an alcohol (e.g., methanol,ethanol, n-butanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol,2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (e.g, methylisobutyl ketone, or methyl ethyl ketone), an ester (e.g., isopropylacetate, or n-butylacetate), a chlorinate solvent (e.g.,1,2-dichloroethane, chlorobenzene, or trifluorotoluene), an aromaticsolvent (e.g., toluene, xylenes, or anisole), water, or combinationsthereof. In some embodiments, the first solvent includes2-methyltetrahydrofuran. In some embodiments, the first solvent can be2-methyltetrahydrofuran.

In some embodiments, the first reaction mixture further includes anadditive. The additive can be 4-dimethylaminopyridine,4-piperidinopyridine, 4-pyrolidinopyridine, imidazole,N-methylimidazole, or 9-azajulolidine. In some embodiments, the additiveis absent.

In general, the first reaction (i.e., step a)) can be performed at anambient to an elevated temperature. For example, the first reactionmixture can be at a temperature of from 30° C. to 150° C. In someembodiments, the first reaction mixture can be at a temperature of from40° C. to 100° C., from 40° C. to 90° C., from 40° C. to 80° C., orabout 80° C. In some embodiments, the first reaction mixture can be at atemperature of from 40° C. to 80° C. In some embodiments, the firstreaction mixture can be at a temperature of about 80° C.

In some embodiments, the method further includes prior to step a):

-   -   a1) forming a third reaction mixture including a compound of        Formula IV:

-   -   -   or a salt thereof, a second base, and a third solvent to            form the compound of Formula III, or the salt thereof,            wherein X is F; and AG¹ is Cl.

The second base can be an aprotic amine (e.g., triethylamine,tri-n-butylamine, N,N′-diisopropylethylamine, N-methylpyrrolidine, orN-methylmorpholine), an aromatic amine (e.g., pyridine, 2,6-lutidine, orcollidine), an inorganic base (e.g., sodium carbonate, sodiumbicarbonate, potassium hydroxide, potassium carbonate, cesium carbonate,or potassium phosphate). The second base can be in an aqueous solution.In some embodiments, the second base includes an aqueous solution ofsodium hydroxide. In some embodiments, the second base can be an aqueoussolution of sodium hydroxide.

The third solvent can be any suitable polar aprotic solvent or non-polarsolvent. The third solvent can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), ahalogenated solvent (e.g., dichloromethane, or 1,2-dichloroethane), anaromatic solvent (benzene, toluene, or xylenes), water, or combinationsthereof. In some embodiments, the third solvent includes2-methyltetrahydrofuran. In some embodiments, the third solvent includes2-methyltetrahydrofuran and water. In some embodiments, the thirdsolvent can be 2-methyltetrahydrofuran. In some embodiments, the thirdsolvent can be 2-methyltetrahydrofuran and water.

The third reaction (i.e., step a1)) can be performed with or without aphase-transfer agent. In some embodiments, the third reaction mixturefurther includes a phase-transfer agent. The phase-transfer agent can bean ammonium salt (e.g., tetra-n-butylammonium bisulfate,tetra-n-butylammonium chloride, tetra-n-butylammonium bromide,benzalkonium chloride, or dodecylethyldimethylammonium bromide). In someembodiments, the phase-transfer agent includes tetra-n-butylammoniumbisulfate. In some embodiments, the phase-transfer agent can betetra-n-butylammonium bisulfate.

In general, the third reaction (i.e., step a1)) can be performed at anysuitable temperature. For example, the third reaction mixture can be ata temperature of from 20° C. to 80° C. In some embodiments, the thirdreaction mixture can be at a temperature of from 20° C. to 70° C., from20° C. to 60° C., from 20° C. to 50° C., or from 20° C. to 40° C. Insome embodiments, the third reaction mixture can be at a temperature offrom 20° C. to 40° C.

In some embodiments, the method further includes prior to step a1):

-   -   a2) forming a fourth reaction mixture including a compound of        Formula V:

-   -   -   or a salt thereof, a first activating agent, and a fourth            solvent to form the compound of Formula IV:

-   -   -   or the salt thereof, wherein X is F; and AG¹ is Cl.

In some embodiments, the first activating agent can be a firstchlorinating agent. The first chlorinating agent can be any suitablechlorinating agent capable of converting the —OH group of Formula V to acorresponding —Cl group (i.e., AG¹ can be Cl in Formula IV). In someembodiments, the first chlorinating agent can be thionyl chloride,oxalyl chloride, phosphorus(V) oxychloride, phosphorus(V) pentachloride,methanesulfonyl chloride, para-toluenesulfonic acid, methanesulfonicanhydride, trifluoromethanesulfonic anhydride, or chlorosulfonic acid.In some embodiments, the first chlorinating agent includes oxalylchloride. In some embodiments, the first chlorinating agent includesthionyl chloride. In some embodiments, the first chlorinating agent canbe oxalyl chloride. In some embodiments, the first chlorinating agentcan be thionyl chloride.

The fourth solvent can be any suitable polar aprotic solvent and/ornon-polar solvents. The fourth solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, or1,4-dioxane), a halogenated solvent (e.g, dichloromethane, or1,2-dichloroethane), an aromatic solvent (e.g., benzene, toluene, orxylenes), or combinations thereof. In some embodiments, the fourthsolvent includes 2-methyltetrahydrofuran. In some embodiments, thefourth solvent can be 2-methyltetrahydrofuran.

In general, the fourth reaction (i.e., step a2)) can be performed at anysuitable temperature. For example, the fourth reaction mixture can be ata temperature of from 0° C. to 80° C. In some embodiments, the fourthreaction mixture can be at a temperature of from 20° C. to 80° C., from30° C. to 80° C., from 40° C. to 80° C., from 50° C. to 80° C., or from50° C. to 70° C. In some embodiments, the fourth reaction mixture can beat a temperature of from 50° C. to 70° C.

In some embodiments, the method further includes prior to step a2) ora1-2):

-   -   a3) forming a sixth reaction mixture including a compound of        Formula VII:

-   -   -   or a salt thereof, a compound of Formula VI:

-   -   -   or a salt thereof, a third base, and a sixth solvent to form            the compound of Formula V or the salt thereof, wherein X is            F.

The compound of Formula VI can be in any suitable form. In someembodiments, the compound of Formula VI can be in a neutral form. Insome embodiments, the compound of Formula VI can be in a salt form. Insome embodiments, the compound of Formula VI can be a tosylate saltthereof.

The third base can be a tertiary amine (e.g., triethylamine,tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, orN-methylmorpholine), an aromatic amine (e.g., pyridine, 2,6-lutidine, orcollidine), or an inorganic base (e.g., sodium carbonate, sodiumbicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate,cesium carbonate, or potassium phosphate tribasic). In some embodiments,the third base can be in an aqueous solution. In some embodiments, thethird base includes potassium carbonate. In some embodiments, the thirdbase includes an aqueous solution of potassium carbonate. In someembodiments, the third base can be potassium carbonate. In someembodiments, the third base can be an aqueous solution of potassiumcarbonate.

The sixth solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the sixth solvent furtherincludes water. In some embodiments, the sixth reaction (i.e., step a3))can be a biphasic reaction. In some embodiments, the sixth solvent canbe an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyltert-butyl ether, or 1,4-dioxane), a halogenated solvent (e.g.,dichloromethane, or 1,2-dichloroethane), an aromatic solvent (e.g.,benzene, toluene, or xylenes), water, or combinations thereof. In someembodiments, the sixth solvent includes 2-methyltetrahydrofuran. In someembodiments, the sixth solvent includes 2-methyltetrahydrofuran andwater. In some embodiments, the sixth solvent can be2-methyltetrahydrofuran. In some embodiments, the sixth solvent can be2-methyltetrahydrofuran and water.

In general, the sixth reaction (i.e., step a3)) can be performed at anysuitable temperature. For example, the sixth reaction mixture can be ata temperature of from 0° C. to 60° C. In some embodiments, the sixthreaction mixture can be at a temperature of from 0° C. to 60° C., from10° C. to 50° C., from 10° C. to 40° C., from 20° C. to 40° C., from 20°C. to 30° C., or about 20° C. In some embodiments, the sixth reactionmixture can be at a temperature of from 20° C. to 30° C. In someembodiments, the sixth reaction mixture can be at a temperature of about20° C.

In some embodiments, the method further includes prior to step a3):

-   -   a4) forming a seventh reaction mixture including a compound of        Formula VIII:

-   -   -   or a salt thereof, a second chlorinating agent, a promoter,            and a seventh solvent to form the compound of Formula VII or            the salt thereof, wherein X is F.

The second chlorinating agent can be any suitable chlorinating agentcapable of converting the —C(O)OH group of Formula VIII to the —C(O)Clgroup of Formula VII. In some embodiments, the second chlorinating agentcan be oxalyl chloride, thionyl chloride, phosphorus(V) oxychloride,phosphorus(V) pentachloride, (chloromethylene)dimethyliminium chloride,1,1′-carbonyldiimidazole, or isobutyl chloroformate. In someembodiments, the second chlorinating agent includes oxalyl chloride. Insome embodiments, the second chlorinating agent includes thionylchloride. In some embodiments, the second chlorinating agent can beoxalyl chloride. In some embodiments, the second chlorinating agent canbe thionyl chloride.

In some embodiments, the promoter can be N,N-dimethylformamide ordichloromethylene-dimethyliminium chloride. In some embodiments, thepromoter includes N,N-dimethylformamide. In some embodiments, thepromoter can be N,N-dimethylformamide.

The seventh solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the seventh solvent can be anether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butylether, or 1,4-dioxane), a halogenated solvent (e.g., dichloromethane, or1,2-dichloroethane), an aromatic solvent (e.g., benzene, toluene, orxylenes), water, or combinations thereof. In some embodiments, theseventh solvent includes 2-methyltetrahydrofuran. In some embodiments,the seventh solvent can be 2-methyltetrahydrofuran.

In general, the seventh reaction (i.e., step a4)) can be performed atany suitable temperature. For example, the seventh reaction mixture canbe at a temperature of from 0° C. to 60° C. In some embodiments, theseventh reaction mixture can be at a temperature of from 0° C. to 60°C., from 10° C. to 50° C., from 10° C. to 40° C., from 20° C. to 40° C.,from 20° C. to 30° C., or about 20° C. In some embodiments, the seventhreaction mixture can be at a temperature of from 20° C. to 30° C. Insome embodiments, the seventh reaction mixture can be at a temperatureof about 20° C.

The compound of Formula II can be deprotected by various methods knownin the art to provide the compound of Formula I or a salt thereof. Insome embodiments, when PG is 2,4-dimethoxybenzyl, the compound ofFormula II can be deprotected by various methods, for example, underacidic, reductive (hydrogenolysis), or oxidative conditions to providethe compound of Formula I or the salt thereof, as described herein.

9. Embodiments of Formula I, II, III, IV, V, VII, and VIII

In some embodiments of any one of formulae I, II, III, IV, V, VII, andVIII, R² can be Cl, F, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; and R¹ andR³ can each independently be hydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, orC₁₋₃ alkoxy. The C₁₋₃ alkyl can be methyl, ethyl, n-propyl, orisopropyl. The C₁₋₃ alkoxy can be methoxy, ethoxy, n-propoxy, orisopropoxy. In some embodiments of any one of formulae I, II, III, IV,V, VII, and VIII, R² can be Cl, F, CN, CF₃, methyl, ethyl, n-propyl,isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy; and R¹ and R³ caneach independently be hydrogen, F, Cl, CN, CF₃, methyl, ethyl, n-propyl,isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy. In someembodiments of any one of formulae I, II, III, IV, V, VII, and VIII, R²can be Cl, F, CN, CF₃, methyl, ethyl, n-propyl, isopropyl, methoxy,ethoxy, n-propoxy, or isopropoxy; and R¹ and R³ can each be hydrogen. Insome embodiments of any one of formulae I, II, III, IV, V, VII, andVIII, R² can be F, and R¹ and R³ can each be hydrogen.

In some embodiments of any one of formulae I, II, III, IV, V, and VI, R⁴can be hydrogen. In some embodiments of any one of formulae I, II, III,IV, V, and VI, R⁴ can be methyl.

In some embodiments of any one of formulae I, II, III, IV, V, and VI, R⁵can be C₃₋₆ alkyl. In some embodiments of any one of formulae I, II,III, IV, V, and VI, R⁵ can be n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In someembodiments of any one of formulae I, II, III, IV, V, and VI, R⁵ can ben-butyl.

In some embodiments of any one of formulae I, II, III, IV, V, and VI, R⁴can be methyl; and R⁵ can be C₃₋₆ alkyl. In some embodiments of any oneof formulae I, II, III, IV, V, and VI, R⁴ can be methyl; and R⁵ can ben-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, or hexyl. In some embodiments of any one of formulae I, II,III, IV, V, and VI, R⁴ can be methyl; and R⁵ can be n-butyl.

In some embodiments of any one of formulae III, IV, V, VII, and VIII, Xcan be F, Br, I, or OTs. In some embodiments of any one of formulae III,IV, V, VII, and VIII, X can be Br. In some embodiments of any one offormulae III, IV, V, VII, and VIII, X can be F.

In some embodiments, the compound of Formula I can be of Formula Ia:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula I can be of Formula Ib:

or a salt thereof.

In some embodiments, the compound of Formula II can be of Formula IIa:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula II can be of Formula IIb:

or a salt thereof.

In some embodiments, the compound of Formula III can be of Formula IIIa:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula III can be of FormulaIIIa-1:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula III can be of Formula IIIb:

or a salt thereof.

In some embodiments, the compound of Formula III can be of FormulaIIIb-1:

or a salt thereof.

In some embodiments, the compound of Formula IV can be of Formula IV-1:

or a salt thereof, wherein R¹, R², R³, R⁴, R⁵, and X are defined anddescribed herein.

In some embodiments, the compound of formula IV-1 can be of FormulaIVa-1:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of formula IV-1 can be of FormulaIVa-2:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula IV-1 can be of FormulaIVb-1:

or a salt thereof.

In some embodiments, the compound of Formula IV-1 can be of FormulaIVb-2:

or a salt thereof.

In some embodiments, the compound of Formula V can be of Formula Va:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula V can be of Formula Va-1:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula V can be of Formula Vb:

or a salt thereof.

In some embodiments, the compound of Formula V can be of Formula Vb-1:

or a salt thereof.

In some embodiments, the compound of Formula VI can be of Formula VIa:

or a salt thereof, wherein R⁵ are defined and described herein.

In some embodiments, the compound of Formula VI can be of Formula VIb:

In some embodiments, the compound of Formula VII can be of Formula VIIa:

or a salt thereof, wherein R² are defined and described herein.

In some embodiments, the compound of Formula VII can be of FormulaVIIa-1:

or a salt thereof, wherein R² are defined and described herein.

In some embodiments, the compound of Formula VII can be of Formula VIIb:

or a salt thereof.

In some embodiments, the compound of Formula VII can be of FormulaVIIb-1:

or a salt thereof.

In some embodiments, the compound of Formula VIII can be of FormulaVIIIa:

or a salt thereof, wherein R² is defined and described herein.

In some embodiments, the compound of Formula VIII can be of FormulaVIIIa-1:

or a salt thereof, wherein R² is defined and described herein.

In some embodiments, the compound of Formula VIII can be of FormulaVIIIb:

or a salt thereof.

In some embodiments, the compound of Formula VIII can be of FormulaVIIIb-1:

or a salt thereof.

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, the method including:

-   -   a4) forming a seventh reaction mixture including a compound of        Formula VIIIb:

-   -   -   or a salt thereof, oxalyl chloride, N,N-dimethylformamide,            2-methyltetrahydrofuran to form a compound of Formula VIIb:

-   -   -   or a salt thereof;

    -   a3) forming a sixth reaction mixture including the compound of        Formula VIIb or the salt thereof, a compound of Formula VIb:

-   -   -   aqueous potassium carbonate, 2-methyltetrahydrofuran, and            water to form a compound of Formula Vb:

-   -   -   or a salt thereof,

    -   a2) forming a fourth reaction mixture including the compound of        Formula Vb or the salt thereof, thionyl chloride, and        2-methyltetrahydrofuran to form a compound of Formula IVb-1:

-   -   -   or a salt thereof;

    -   a1) forming a third reaction mixture including the compound of        Formula IVb-1 or the salt thereof, aqueous sodium hydroxide,        tetra-n-butylammonium hydrogensulfate, and        2-methyltetrahydrofuran to form a compound of Formula IIIb:

-   -   -   or a salt thereof;

    -   a) forming a first reaction mixture including the compound of        Formula IIIb or the salt thereof, a compound of Formula IXa        wherein n is from 0 to 1:

-   -   -   Cu(II) acetate, potassium phosphate tribasic, cysteine,            2-methyltetrahydrofuran, and acetonitrile to form a compound            of Formula IIb:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture including the compound of        Formula IIb or the salt thereof, trifluoroacetic acid, and        dichloromethane to prepare a trifluoroacetic acid salt of the        compound of Formula Ib:

and

-   -   c) forming a ninth reaction mixture including the        trifluoroacetic acid salt of the compound of Formula Ib, sodium        hydroxide, ethanol, and water to provide the compound of Formula        Ib in a neutral form.

In some embodiments, the compound of Formula IXa can be of Formula IXb:

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, the method including:

-   -   a4) forming a seventh reaction mixture including a compound of        Formula VIIIb-1:

-   -   -   or a salt thereof, oxalyl chloride, N,N-dimethylformamide,            2-methyltetrahydrofuran to form a compound of Formula            VIIb-1:

-   -   -   or a salt thereof;

    -   a3) forming a sixth reaction mixture including the compound of        Formula VIIb-1 or the salt thereof, a compound of Formula VIb:

-   -   -   aqueous potassium carbonate, 2-methyltetrahydrofuran, and            water to form a compound of Formula Vb-1:

-   -   -   or a salt thereof,

    -   a2) forming a fourth reaction mixture including the compound of        Formula Vb-1 or the salt thereof, thionyl chloride, and        2-methyltetrahydrofuran to form a compound of Formula IVb-2:

-   -   -   or a salt thereof;

    -   a1) forming a third reaction mixture including the compound of        Formula IVb-2 or the salt thereof, aqueous sodium hydroxide,        tetra-n-butylammonium hydrogensulfate, and        2-methyltetrahydrofuran to form a compound of Formula IIIb-1:

-   -   -   or a salt thereof;

    -   a) forming a first reaction mixture including the compound of        Formula IIIb-1 or the salt thereof, a compound of Formula IXc:

-   -   -   cesium carbonate, and 2-methyltetrahydrofuran to form a            compound of Formula IIb:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture including the compound of        Formula IIb or the salt thereof, trifluoroacetic acid, and        dichloromethane to prepare a trifluoroacetic acid salt of the        compound of Formula Ib:

-   -   c) forming a ninth reaction mixture including the        trifluoroacetic acid salt of the compound of Formula Ib, sodium        hydroxide, ethanol, and water to provide the compound of Formula        Ib in a neutral form.

In some embodiments, the compound of Formula Vb or Vb-1, or the saltthereof can be isolated in a solution including 2-methyltetrahydrofuranand used in the following step a2) without purification and/or removalof the 2-methyltetrahydrofuran. In some embodiments, the compound ofFormula IVb-1 or IVb-2, or the salt thereof can be isolated in asolution including 2-methyltetrahydrofuran and used in the followingstep a1) without purification and/or removal of the2-methyltetrahydrofuran. In some embodiments, the compound of FormulaIIIb or IIIb-1, or the salt thereof can be isolated in a solutionincluding 2-methyltetrahydrofuran and used in the following step a)without purification and/or removal of the 2-methyltetrahydrofuran. Insome embodiments, the compound of Formula Vb or Vb-1, or the saltthereof, the compound of Formula IVb-1 or IVb-2, or the salt thereof,and the compound of Formula IIIb or IIIb-1, or the salt thereof can eachbe isolated in a solution including 2-methyltetrahydrofuran and used inthe following step without purification and/or removal of2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vbor Vb-1, or the salt thereof can be isolated in a solution including2-methyltetrahydrofuran and used in the following step a2) withoutremoval of the 2-methyltetrahydrofuran. In some embodiments, thecompound of Formula IVb-1 or IVb-2, or the salt thereof can be isolatedin a solution including 2-methyltetrahydrofuran and used in thefollowing step a1) without removal of the 2-methyltetrahydrofuran. Insome embodiments, the compound of Formula IIIb or IIIb-1, or the saltthereof can be isolated in a solution including 2-methyltetrahydrofuranand used in the following step a) without removal of the2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vbor Vb-1, or the salt thereof, the compound of Formula IVb-1 or IVb-2, orthe salt thereof, and the compound of Formula IIIb or IIIb-1, or thesalt thereof can each be isolated in a solution including2-methyltetrahydrofuran and used in the following step without removalof 2-methyltetrahydrofuran.

In some embodiments, the compound of Formula Vb or the salt thereof canbe isolated in a solution including 2-methyltetrahydrofuran and used inthe following step a2) without purification and/or removal of the2-methyltetrahydrofuran. In some embodiments, the compound of FormulaIVb-1 or the salt thereof can be isolated in a solution including2-methyltetrahydrofuran and used in the following step a1) withoutpurification and/or removal of the 2-methyltetrahydrofuran. In someembodiments, the compound of Formula IIIb or the salt thereof can beisolated in a solution including 2-methyltetrahydrofuran and used in thefollowing step a) without purification and/or removal of the2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vbor the salt thereof, the compound of Formula IVb-1 or the salt thereof,and the compound of Formula IIIb or the salt thereof can each beisolated in a solution including 2-methyltetrahydrofuran and used in thefollowing step without purification and/or removal of2-methyltetrahydrofuran. In some embodiments, the compound of Formula Vbor the salt thereof can be isolated in a solution including2-methyltetrahydrofuran and used in the following step a2) withoutremoval of the 2-methyltetrahydrofuran. In some embodiments, thecompound of Formula IVb-1 or the salt thereof can be isolated in asolution including 2-methyltetrahydrofuran and used in the followingstep a1) without removal of the 2-methyltetrahydrofuran. In someembodiments, the compound of Formula IIIb or the salt thereof can beisolated in a solution including 2-methyltetrahydrofuran and used in thefollowing step a) without removal of the 2-methyltetrahydrofuran. Insome embodiments, the compound of Formula Vb or the salt thereof, thecompound of Formula IVb-1 or the salt thereof, and the compound ofFormula IIIb or the salt thereof can each be isolated in a solutionincluding 2-methyltetrahydrofuran and used in the following step withoutremoval of 2-methyltetrahydrofuran.

In some embodiments, the compound of Formula VIIb or VIIb-1, or the saltthereof can be formed in situ and used in the following step a3) withoutpurification and/or removal of 2-methyltetrahydrofuran. In someembodiments, the compound of Formula VIIb or VIIb-1, or the salt thereofcan be formed in situ and used in the following step a3) without removalof 2-methyltetrahydrofuran.

In some embodiments, the compound of Formula VIIb or the salt thereofcan be formed in situ and used in the following step a3) withoutpurification and/or removal of 2-methyltetrahydrofuran. In someembodiments, the compound of Formula VIIb or the salt thereof can beformed in situ and used in the following step a3) without removal of2-methyltetrahydrofuran.

In some embodiments, the compound of Formula VIIb or VIIb-1, or the saltthereof, the compound of Formula Vb or Vb-1, or the salt thereof, thecompound of Formula IVb-1 or IVb-2, or the salt thereof, and thecompound of Formula IIIb or IIIb-1, or the salt thereof can each beisolated in a solution including 2-methyltetrahydrofuran and used in thefollowing step without purification and/or removal of2-methyltetrahydrofuran. In some embodiments, the compound of FormulaVIIb or VIIb-1, or the salt thereof, the compound of Formula Vb or Vb-1,or the salt thereof, the compound of Formula IVb-1 or IVb-2, or the saltthereof, and the compound of Formula IIIb or IIIb-1, or the salt thereofcan each be isolated in a solution including 2-methyltetrahydrofuran andused in the following step without removal of 2-methyltetrahydrofuran.

In some embodiments, the compound of Formula VIIb or the salt thereof,the compound of Formula Vb or the salt thereof, the compound of FormulaIVb-1 or the salt thereof, and the compound of Formula IIIb or the saltthereof can each be isolated in a solution including2-methyltetrahydrofuran and used in the following step withoutpurification and/or removal of 2-methyltetrahydrofuran. In someembodiments, the compound of Formula VIIb or the salt thereof, thecompound of Formula Vb or the salt thereof, the compound of FormulaIVb-1 or the salt thereof, and the compound of Formula IIIb or the saltthereof can each be isolated in a solution including2-methyltetrahydrofuran and used in the following step without removalof 2-methyltetrahydrofuran.

B. Method of Preparing Compounds of Formula I from Formula V

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula II:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula V:

-   -   -   or a salt thereof, a compound having the Formula            PG-NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent to form the            compound of Formula II, or a salt thereof,            wherein R¹, R², and R³ can each independently be hydrogen,            F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be            hydrogen or methyl; R⁵ can be C₃₋₆ alkyl; X can be F, Cl,            Br, I, or OTs; and PG can be an amino protecting group.

The compound having the Formula PG-NHC(═NH)NH₂ can be in any suitableform. In some embodiments, the compound having the FormulaPG-NHC(═NH)NH₂ can be in a neutral form. In some embodiments, thecompound having the Formula PG-NHC(═NH)NH₂ can be in a salt form. Insome embodiments, the compound having the Formula PG-NHC(═NH)NH₂ can bea hemisulfate, a sulfate, a chloride, a bromide, a carbonate, a nitrate,or an acetate salt thereof. In some embodiments, the compound having theFormula PG-NHC(═NH)NH₂ can be of Formula IX:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula IX can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula IX can be a hemisulfate salt wherein n can be ½.

In some embodiments, PG can be an amino protecting group. Suitable aminoprotecting groups include, but are not limited to, a carbobenzyloxy(Cbz) group, a p-methoxybenzyl carbonyl (Moz or MeOZ) group, atert-Butyloxycarbonyl (BOC) group, a 2-trimethylsilylethyoxymethyl (SEM)group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, an acetyl (Ac)group, a benzoyl (Bz) group, a benzyl (Bn) group, a carbamate group, ap-methoxybenzyl (PMB) group, a 2,4-dimethoxybenzyl group (DMB), a1-(2,4-dimethoxyphenyl)ethyl, a 3,4-dimethoxybenzyl (DMPB) group, ap-methoxyphenyl (PMP) group, a tosyl (Ts) group, a Troc (trichloroethylchloroformate) group, and other sulfonamides (Nosyl & Nps) groups. Insome embodiments, PG can be 2,4-dimethoxybenzyl.

In some embodiments, the compound of Formula IX can be of Formula IXa:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula IXa can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula IXa can be a hemisulfate salt having Formula IXb:

In some embodiments, X can be Br. In some embodiments, the compound ofFormula V can be the compound of Formula Vb.

In some embodiments, the first transition-metal catalyst can be acompound that includes one or more transition metals or transition metalcations. Suitable transition metals include, but are not limited to, Sc,Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag,Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg and Ac. Suitable transitionmetal cations include, but are not limited to, Cd²⁺, Co²⁺, Co⁺, Cr²⁺,Cr⁺, Cu⁺ (i.e., Cu(I)), Cu²⁺ (i.e., Cu(II)), Fe²⁺, Fe⁺, Mn²⁺, Mn⁺, Ni²⁺,Ni⁺, Pd²⁺ (i.e., Pd(II)), and Zn²⁺. In some embodiments, the firsttransition-metal catalyst includes a copper metal, a copper oxide, acopper (I) salt, a copper (II) salt, or combinations thereof. In someembodiments, the first transition-metal catalyst includes a copper (I)salt. In some embodiments, the first transition-metal catalyst can be acopper (I) salt. In some embodiments, the first transition-metalcatalyst includes a copper (II) salt. In some embodiments, the firsttransition-metal catalyst can be a copper (II) salt. In someembodiments, the first transition-metal catalyst can be Cu(I) iodide,Cu(I) bromide, Cu(I) chloride, Cu(I) acetate, Cu(I) carbonate, Cu(I)nitrate, Cu(I) sulfate, Cu(I) phosphate, Cu(I) 3-methylsalicylate, Cu(I)thiophene-2-carboxylate, Cu(I) oxide, Cu(II) iodide, Cu(II) bromide,Cu(II) chloride, Cu(II) acetate, Cu(II) carbonate, Cu(II) nitrate,Cu(II) sulfate, Cu(II) pyrophosphate, Cu(II) phosphate, Cu(II) tartrate,Cu(II) oxide, or combinations thereof. In some embodiments, the firsttransition-metal catalyst can be Cu(II) iodide, Cu(II) bromide, Cu(II)chloride, Cu(II) acetate, Cu(II) carbonate, Cu(II) nitrate, Cu(II)sulfate, Cu(II) pyrophosphate, Cu(II) phosphate, Cu(II) tartrate, Cu(II)oxide, or combinations thereof. In some embodiments, the firsttransition-metal catalyst includes Cu(I) iodide. In some embodiments,the first transition-metal catalyst can be Cu(I) iodide.

The first base can be an alkali carbonate, an alkali bicarbonate, analkali phosphate tribasic, a carboxylate, an amidine-based compound, orcombinations thereof. Suitable alkali carbonates include lithiumcarbonate, sodium carbonate, potassium carbonate, and cesium carbonate.Suitable alkali bicarbonates include lithium bicarbonate, sodiumbicarbonate, and potassium bicarbonate. Suitable alkali phosphatestribasic include sodium phosphate tribasic and potassium phosphatetribasic. Suitable carboxylates include, but are not limited to, lithiumacetate, sodium acetate, potassium acetate, cesium acetate, potassiumtrimethylacetate, and tetrabutylphosphonium malonate. Suitableamidine-based compounds include, but are not limited to,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and1,5-diazabicyclo[4.3.0]non-5-en (DBN). In some embodiments, the firstbase can be lithium carbonate, sodium carbonate, potassium carbonate,cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassiumbicarbonate, sodium phosphate tribasic, potassium phosphate tribasic,potassium acetate, potassium trimethylacetate, tetrabutylphosphoniummalonate, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-en, or combinations thereof. In someembodiments, the first base includes potassium phosphate tribasic. Insome embodiments, the first base can be potassium phosphate tribasic.

The first solvent can be any suitable polar or non-polar, protic oraprotic solvent. In some embodiments, the first solvent can beacetonitrile, propionitrile, N,N-dimethylacetamide,N-methyl-2-pyrrolidinone, dimethylsulfoxide, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether,isopropanol, 2-methylbutan-2-ol, ethyl acetate, isopropyl acetate,methyl isobutyl ketone, toluene, trifluorotoluene, xylenes, orcombinations thereof. In some embodiments, the first solvent includesacetonitrile. In some embodiments, the first solvent can beacetonitrile.

In some embodiments, the first reaction mixture further includes a firstligand. In some embodiments, the first ligand can be an amino acid, apolypyridyl ligand, or a tertiary amine. Suitable amino acids includenaturally occurring and synthetic amino acids, as well as amino acidanalogs that function in a manner similar to the naturally occurringamino acids. Suitable polypyridyl ligands include, but are not limitedto, 2,2′-bipyridine, 1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine,6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine,2,2′-bipyridine-4,4′-dicarboxylic acid and 2,2′:6′2″-terpyridine.Suitable tertiary amines include, but are not limited to, triethylamine,tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine,N-methylmorpholine, 1,4-diazabicylo[2.2.2]-octane, andN,N,N′,N′-tetramethylethylenediamine. In some embodiments, the firstligand can be arginine, histidine, lysine, aspartic acid, glutamic acid,serine, threonine, asparagine, glutamine, cysteine, selenocysteine,glycine, proline, alanine, valine, isoleucine, leucine, methionine,phenylalanine, tyrosine, tryptophan, α-(methylamino)isobutyric acid,(4-methyl-1-piperazinyl)acetic acid, N-acetyl-cysteine, 2,2′-bipyridine,1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine,6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine,2,2′-bipyridine-4,4′-dicarboxylic acid,N,N,N′,N′-tetramethylethylenediamine, or combinations thereof. In someembodiments, the first ligand includes 2,2′-bipyridine,1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine,6,6′-dimethyl-2,2′-bipyridine, 4,4′-di-tert-butyl-2,2-bipyridine,2,2′-bipyridine-4,4′-dicarboxylic acid and 2,2′:6′2″-terpyridine. Insome embodiments, the first ligand includes 2,2′-bipyridine. In someembodiments, the first ligand can be 2,2′-bipyridine.

In some embodiments, the first reaction mixture further includes adehydrating agent or additive. In some embodiments, the dehydratingagent or additive can be a 3 Å sieve, a 4 Å sieve, a 5 Å sieve, or asilica gel. In some embodiments, the dehydrating agent or additive canbe a 3 Å sieve.

In general, the first reaction (i.e., step a)) can be performed at anambient to an elevated temperature. For example, the first reactionmixture can be at a temperature of from 30° C. to 110° C. or heated toreflux. In some embodiments, the first reaction mixture can be at atemperature of from 40° C. to 100° C., from 50° C. to 100° C., from 50°C. to 90° C., from 60° C. to 90° C., from 70° C. to 90° C., or about 80°C. In some embodiments, the first reaction mixture can be at atemperature of from 50° C. to a reflux temperature. In some embodiments,the first reaction mixture can be heated to reflux.

Once the first reaction is complete, the first transition metal catalystcan be removed from the reaction mixture by a second ligand, forexample, ethylenediaminetetraacetic acid (EDTA) or EDTA disodium salt.In some embodiments, upon completion of the first reaction, the firsttransition metal catalyst can be removed from the first reaction mixtureusing a second ligand. In some embodiments, the second ligand includesethylenediaminetetraacetic acid or a salt thereof. In some embodiments,upon completion of the first reaction, the first transition metalcatalyst can be removed from the first reaction mixture usingethylenediaminetetraacetic acid or a salt thereof. In some embodiments,upon completion of the first reaction, Cu(I) can be removed from thefirst reaction mixture using ethylenediaminetetraacetic acid disodiumsalt.

The compound of Formula II can be deprotected by various methods knownin the art to provide the compound of Formula I or a salt thereof. WhenPG is 2,4-dimethoxybenzyl, the compound of Formula II can be deprotectedby various methods, for example, under acidic, reductive(hydrogenolysis), or oxidative conditions to provide the compound ofFormula I or the salt thereof, as described in Section-1 underSection-A.

C. Method of Preparing Compounds of Formula I from Formula III ViaUnprotected Guanidine

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, comprising:

-   -   a) forming a first reaction mixture comprising a compound of        Formula III:

-   -   -   a compound having the Formula H₂NC(═NH)NH₂ or a salt            thereof, a first base, and a first solvent to form the            compound of Formula I or the salt thereof,            wherein R¹, R², and R³ can each independently be hydrogen,            F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be            hydrogen or methyl; R⁵ can be C₃₋₆ alkyl; and X can be F,            Cl, Br, I, or OTs.

In some embodiments, X can be F.

The compound having the Formula H₂NC(═NH)NH₂ can be in any suitableform. In some embodiments, the compound having the Formula H₂NC(═NH)NH₂can be in a neutral form. In some embodiments, the compound having theFormula H₂NC(═NH)NH₂ can be in a salt form. In some embodiments, thecompound having the Formula H₂NC(═NH)NH₂ can be a hemisulfate, asulfate, a chloride, a bromide, a carbonate, a nitrate, or an acetatesalt thereof. In some embodiments, the compound having the FormulaH₂NC(═NH)NH₂ can be of Formula XIV:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula XIV can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula XIV can be a hemisulfate salt wherein n can be ½.

In some embodiments, the first base can be absent or present. The firstbase, when present, can be a carbonate (e.g., cesium carbonate, sodiumcarbonate, potassium carbonate, rubidium carbonate, magnesium carbonate,calcium carbonate, strontium carbonate, barium carbonate, or ammoniumcarbonate), a metal oxide (e.g., magnesium oxide), a hydroxide (e.g.,potassium hydroxide, sodium hydroxide, lithium hydroxide, cesiumhydroxide, barium hydroxide, ammonium hydroxide, ortetra-n-butylammonium hydroxide), lithium phenoxide, a silanolate (e.g,potassium trimethylsilanolate, sodium trimethylsilanolate, lithiumsilanolate, or sodium dimethylphenylsilanolate), a phosphate (e.g.,potassium phosphate tribasic, calcium phosphate tribasic, magnesiumphosphate tribasic, sodium phosphate tribasic, sodium phosphate dibasic,or potassium phosphate dibasic), a hydride (e.g., sodium hydride orpotassium hydride), an amine (e.g., 1,4-diazabicyclo[2.2.2]octane,1-azabicyclo[2.2.2]octane, 1,8-diaza[5.4.0]undec-7-ene and1,5-diazabicyclo[4.3.0]non-5-ene pyridine, 1,1,3,3-tetramethylguanidine,4-methylmorpholine, 2-tert-buty-1,1,3,3-tetramethylguanidine,1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine,1,8-bis(dimethylamino)naphthalene, orN,N,N′N′-tetramethyl-1,8-napthalenediamine), an amide (e.g., lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, lithium diisopropyl amide, sodium diisopropylamide, or lithium dicyclohexylamide), an alkylmetal (e.g.,n-butyllithium, tert-butyllithium, methyllithium, phenyllithium, lithiumnaphthalenide, or sodium naphthalenide), an alkoxide (e.g., magnesiumtert-butoxide, potassium tert-butoxide, sodium tert-butoxide, sodiumtert-pentoxide, or potassium tert-pentoxide), a phosphorane (e.g.,tert-butylimino-tri(pyrrolidino)phosphorene,2-tert-butylimino-tri(pyrrolidino)phosphorene, or2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphorene),or combinations thereof. In some embodiments, the first base can belithium carbonate, sodium carbonate, potassium carbonate, cesiumcarbonate, lithium bicarbonate, sodium bicarbonate, potassiumbicarbonate, sodium phosphate tribasic, potassium phosphate tribasic,potassium acetate, potassium trimethylacetate, tetrabutylphosphoniummalonate, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-en, or combinations thereof. In someembodiments, the first base is present and includes cesium carbonate. Insome embodiments, the first base can be cesium carbonate.

The first solvent can be any suitable polar or non-polar, protic oraprotic solvent. The first solvent can be a polar aprotic solvent (e.g.,N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methylpyrrolidinone,dimethylsulfoxide, sulfolane, acetonitrile, propionitrile,butyronitrile, nitromethane, or nitroethane), an ether (tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, methyl tert-butylether, or cyclopentyl methyl ether), an alcohol (e.g., methanol,ethanol, n-butanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol,2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (e.g, methylisobutyl ketone, or methyl ethyl ketone), an ester (e.g., isopropylacetate, or n-butylacetate), a chlorinate solvent (e.g.,1,2-dichloroethane, chlorobenzene, or trifluorotoluene), an aromaticsolvent (e.g., toluene, xylenes, or anisole), water, or combinationsthereof. In some embodiments, the first solvent can be acetonitrile,propionitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone,dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, cyclopentyl methyl ether, isopropanol, 2-methylbutan-2-ol,ethyl acetate, isopropyl acetate, methyl isobutyl ketone, toluene,trifluorotoluene, xylenes, or combinations thereof. In some embodiments,the first solvent includes N,N′-dimethylacetamide. In some embodiments,the first solvent can be N,N′-dimethylacetamide.

In some embodiments, the first reaction mixture further includes anadditive. The additive can be 4-dimethylaminopyridine,4-piperidinopyridine, 4-pyrolidinopyridine, imidazole,N-methylimidazole, or 9-azajulolidine. In some embodiments, the additiveis absent.

In general, the first reaction (i.e., step a)) can be performed at anambient to an elevated temperature. For example, the first reactionmixture can be at a temperature of from 20° C. to 150° C. In someembodiments, the first reaction mixture can be at a temperature of from30° C. to 100° C., from 40° C. to 100° C., from 50° C. to 90° C., from50° C. to 80° C., from 60° C. to 80° C., or about 80° C. In someembodiments, the first reaction mixture can be at a temperature of from60° C. to 80° C. In some embodiments, the first reaction mixture can beat a temperature of about 80° C.

The compound of Formula III can be prepared according to any one of themethods as described herein. Embodiments of Formula I, III, IV, V, VII,and VIII are as described according to Section-9 under Section-A.

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including the compound of        Formula IIIb-1:

-   -   -   or a salt thereof, a compound of Formula XIVa:

-   -   -   cesium carbonate, and N,N′-dimethylacetamide to form the            compound of Formula Ib or the salt thereof.

D. Method of Preparing Compounds of Formula I Via Guanidine Salt

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula XVIII:

or a salt thereof, comprising:

-   -   a) forming a first reaction mixture comprising a compound of        Formula XV:

-   -   -   a compound of Formula XVI-1:

-   -   -   or a salt thereof, a compound having the Formula            R⁷—NHC(═NH)NH₂ or a salt thereof, a first transition-metal            catalyst, a first base, and a first solvent, to form the            compound of Formula XVIII or the salt thereof,            wherein

    -   R¹, R², and R³ are each independently hydrogen, F, Cl, CN, CF₃,        C₁₋₃ alkyl, or C₁₋₃ alkoxy;

    -   R⁴ is hydrogen or methyl;

    -   R⁵ is C₁₋₆ alkyl;

    -   R⁶ is hydrogen, OH, or O-PG¹;

    -   R⁷ is hydrogen or PG;

    -   X and X¹ are each independently F, Cl, Br, I, or OTs;

    -   PG is an amino protecting group; and

    -   PG1 is a hydroxy protecting group.

In some embodiments, R⁶ can be hydrogen. In some embodiments, R⁶ can beOH.

In some embodiments, the compound of Formula XVIII can be of Formula I:

or a salt thereof, wherein R⁵ is C₃₋₆ alkyl.

In some embodiments, the compound of Formula XVI is of Formula XVIa:

In some embodiments, PG¹ can be a hydroxy protecting group. Suitablehydroxy protecting groups include, but are not limited to, a silyl group(e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl, phenyl dimethylsilyl, di-tert-butylsilyl,[2-(trimethylsilyl)ethoxy]methyl, or 2-trimethylsilyl)ethoxycarbonyl),an acyl group (e.g., acetyl, propionyl, isobutyryl, trimetylacetyl, ortrifluoroacetyl), an aryl group (e.g., phenyl, 4-methoxyphenyl, or4-bromophenyl), an alkyl or heterocycloalkyl group (e.g., allyl,tert-butyl, or tertahydropyranyl), an arylalkyl group (e.g., benzyl,para-methoxybenzyl, or 2,4-dimethoxybenzyl). In some embodiments, PG¹can be 2,4-dimethoxybenzyl.

In some embodiments, R⁷ can be hydrogen. In some embodiments, theFormula R⁷—NHC(═NH)NH₂ can be the Formula H₂NC(═NH)NH₂. The compoundhaving the Formula H₂NC(═NH)NH₂ can be in any suitable form. In someembodiments, the compound having the Formula H₂NC(═NH)NH₂ can be in aneutral form. In some embodiments, the compound having the FormulaH₂NC(═NH)NH₂ can be in a salt form. In some embodiments, the compoundhaving the Formula H₂NC(═NH)NH₂ can be a hemisulfate, a sulfate, achloride, a bromide, a carbonate, a nitrate, or an acetate salt thereof.In some embodiments, the compound having the Formula H₂NC(═NH)NH₂ can beof Formula XIV:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula XIV can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula XIV can be a hemisulfate salt wherein n can be ½.

In some embodiments, R⁷ can be PG. In some embodiments, the FormulaR⁷—NHC(═NH)NH₂ can be the Formula PG-NHC(═NH)NH₂. The compound havingthe Formula PG-NHC(═NH)NH₂ can be in any suitable form. In someembodiments, the compound having the Formula PG-NHC(═NH)NH₂ can be in aneutral form. In some embodiments, the compound having the FormulaPG-NHC(═NH)NH₂ can be in a salt form. In some embodiments, the compoundhaving the Formula PG-NHC(═NH)NH₂ can be a hemisulfate, a sulfate, achloride, a bromide, a carbonate, a nitrate, or an acetate salt thereof.In some embodiments, the compound having the Formula PG-NHC(═NH)NH₂ canbe of Formula IX:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula IX can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula IX can be a hemisulfate salt wherein n can be ½.

In some embodiments, PG can be an amino protecting group. Suitable aminoprotecting groups include, but are not limited to,tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxylcarbonyl,allyloxycarbonyl, acetyl, trifluoroacetyl,2,2,5,7,8-Pentamethyl-chromane-6-sulfonyl chloride,para-toluenesulfonyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl,4-methoxybenzyl, 2-chlorobenzyl, or 2,4-dimethoxybenzyl. In someembodiments, PG can be 2,4-dimethoxybenzyl.

In some embodiments, the compound of Formula IX can be of Formula IXa:

wherein n can be from 0 to 1. In some embodiments, the compound ofFormula IXa can be a hemisulfate salt wherein n can be ½, a sulfate saltwherein n can be 1, or a combination thereof. In some embodiments, thecompound of Formula IXa can be a hemisulfate salt having Formula IXb:

The first transition-metal catalyst can be a compound that includes oneor more transition metals or transition metal cations. Suitabletransition metals include, but are not limited to, Sc, Ti, V, Cr, Mn,Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta,W, Re, Os, Ir, Pt, Au, Hg and Ac. Suitable transition metal cationsinclude, but are not limited to, Cd²⁺, Co²⁺, Co⁺, Cr²⁺, Cr⁺, Cu⁺ (i.e.,Cu(I)), Cu²⁺ (i.e., Cu(II)), Fe²⁺, Fe⁺, Mn²⁺, Mn⁺, Ni²⁺, Ni⁺, Pd²⁺(i.e., Pd(II)), and Zn²⁺. In some embodiments, the firsttransition-metal catalyst includes a Pd catalyst. In some embodiments,the first transition-metal catalyst can be a Pd catalyst. In someembodiments, the first transition-metal catalyst includes a Pd(II)catalyst. In some embodiments, the first transition-metal catalyst canbe a Pd(II) catalyst. In some embodiments, the Pd(II) catalyst can bepalladium(II) acetate, palladium (II) pivolate, palladium (II)propionate, palladium (II) trifloroacetate, palladium (II) bromide,palladium (II) chloride, tris(dibenzylideneacetone)dipalladium(0);bis(acetonitrile)palladium(II) dichloride,(2-Dicyclohexylphosphino-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate, (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate,[(di(1-adamantyl)-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(2-di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II)methanesulfonate,[2-(di-1-adamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl][2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate,[(di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(II)methanesulfonate,mesyl(2-(di-tert-butylphosphino)-1,1′-binaphthyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),methanesulfonato (di-tert-butyl) methylphosphino(2′-amino-1,1′-biphenyl-2-yl) palladium(II), methanesulfonato2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′-biphenyl-2-yl)palladium(II), or combinations thereof. In some embodiments, the firsttransition-metal catalyst includes palladium(II) acetate. In someembodiments, the first transition-metal catalyst can be palladium(II)acetate.

In some embodiments, the first base can be any suitable inorganic ororganic base. In some embodiments, the first base can be a carbonate(e.g., cesium carbonate, lithium carbonate, sodium carbonate, potassiumcarbonate, calcium carbonate, strontium carbonate, barium carbonate, orammonium carbonate), a hydroxide (e.g., potassium hydroxide, sodiumhydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide,ammonium hydroxide, or tetra-n-butylammonium hydroxide), a silanolate(e.g., potassium trimethylsilanolate, sodium trimethylsilanolate,lithium silanolate, or sodium dimethylphenylsilanolate), a phosphate(e.g., potassium phosphate tribasic, calcium phosphate tribasic,magnesium phosphate tribasic, sodium phosphate tribasic, sodiumphosphate dibasic, or potassium phosphate dibasic), a carboxylate (e.g.,sodium acetate, potassium acetate, potassium trimethyl acetate, orpotassium propionate), an alkoxide (e.g., sodium tert-butoxide,potassium tert-butoxide, or sodium tert-pentoxide), an amine (e.g.,N,N-diisopropylethyl amine, triethylamine,N,N,N′,N′-tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane,1-azabicyclo[2.2.2]octane, 1,8-diaza[5.4.0]undec-7-ene and1,5-diazabicyclo[4.3.0]non-5-ene pyridine, 1,1,3,3-tetramethylguanidine,4-methylmorpholine, 2-tert-buty-1,1,3,3-tetramethylguanidine,1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido[1,2-a]pyrimidine,1,8-bis(dimethylamino)naphthalene, orN,N,N′N′-tetramethyl-1,8-napthalenediamine), an amide (e.g., lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, lithium diisopropyl amide, sodium diisopropylamide, lithium dicyclohexylamide), or combinations thereof. In someembodiments, the first base can be cesium carbonate, lithium carbonate,sodium carbonate, potassium carbonate, calcium carbonate, strontiumcarbonate, barium carbonate, or ammonium carbonate, or combinationsthereof. In some embodiments, the first base can be lithium carbonate,sodium carbonate, potassium carbonate, cesium carbonate, or combinationsthereof. In some embodiments, the first base includes cesium carbonate.In some embodiments, the first base can be cesium carbonate.

In some embodiments, the first solvent can be any suitable polar ornon-polar, protic or aprotic solvent. In some embodiments, the firstsolvent can be a polar aprotic solvent (e.g., N,N′-dimethylformamide,N,N′-dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide,sulfolane, acetonitrile, propionitrile, butyronitrile, nitromethane, ornitroethane), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, dibutyl ether, methyl tert-butyl ether, or cyclopentylmethyl ether), an alcohol (e.g., 2-propanol, 2-butanol, tert-butanol,2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), aketone (e.g., methyl isobutyl ketone, or methyl ethyl ketone), an ester(e.g., isopropyl acetate, or n-butylacetate), a chlorinate solvent(1,2-dichloroethane, chlorobenzene, or trifluorotoluene), an aromaticsolvent (toluene, xylenes, or anisole), or combinations thereof. In someembodiments, the first solvent can be toluene, trifluorotoluene,chlorobenzene, xylenes, anisole, or combinations thereof. In someembodiments, the first solvent includes toluene. In some embodiments,the first solvent can be toluene.

In some embodiments, the first reaction mixture further includes a firstligand. In some embodiments, the first ligand can be1,3-bis(dicyclohexylphosphino)propane, 1,2-bis(dimethylphosphino)ethane,bis(diphenylphosphino)methane, di(1-adamantyl)-n-butylphosphine,2-(dicyclohexylphosphino)biphenyl, triphenylphosphine,tri-ortho-tolylphosphine, tri-tert-butylphosphine,di-tert-butyl-(methyl)phosphine, di-tert-butyl(phenyl)phosphine,tricyclohexylphosphine, tri-isopropylphosphine,n-butyldiadamantylphosphine,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,bis[(2-diphenylphosphino)phenyl]ether,1,1′-bis(diphenlphosphino)ferrocene,(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene,1,3-bis(diphenylphosphino)propane,5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole,di(1-adamantyl)-2-morpholinophenylphosphine,N,N′-(2,6-diisopropylphenyl)dihydroimidazolium chloride,(2-biphenyl)di-tert-butylphosphine,(2-biphenylyl)di-tert-butylphosphine,2-(di-tert-butylphosphino)biphenyl, (2-biphenyl)dicyclohexylphosphine,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl,2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl,2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl,2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl,2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl,or a tetrafluoroborate salt thereof. In some embodiments, the firstligand includes 1,3-bis(dicyclohexylphosphino)propane. In someembodiments, the first ligand can be1,3-bis(dicyclohexylphosphino)propane.

In general, the first reaction (i.e., step a)) can be performed at anambient to an elevated temperature. For example, the first reactionmixture can be at a temperature of from 50° C. to 120° C. In someembodiments, the first reaction mixture can be at a temperature of from40° C. to 120° C., from 50° C. to 120° C., from 60° C. to 120° C., from60° C. to 110° C., from 70° C. to 110° C., or about 90° C. In someembodiments, the first reaction mixture can be at a temperature of from70° C. to 110° C. In some embodiments, the first reaction mixture can beat about 90° C.

In some embodiments, once the first reaction is complete, the firsttransition metal catalyst can be removed from the reaction mixture byfiltration through a silica gel.

In some embodiments, the compound of Formula I can be of Formula Ia:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula I can be of Formula Ib:

or a salt thereof.

In some embodiments, the compound of Formula XV can be of Formula XVa:

or a salt thereof, wherein R² and X are defined and described herein.

In some embodiments, the compound of Formula XV can be of Formula XVb:

or a salt thereof.

In some embodiments, the compound of Formula XVI-1 or XVI-2 can be ofFormula XVIa

or a salt thereof, wherein R⁴ and R⁵ are defined and described herein.

In some embodiments, the compound of Formula XVI-1 or XVI-2 can be ofFormula XVIb

or a salt thereof, wherein R⁵ is defined and described herein.

In some embodiments, the compound of Formula XVI-1 or XVI-2 can be ofFormula XVIc

or a salt thereof.

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, comprising:

-   -   a) forming a first reaction mixture comprising a compound of        Formula XVb:

-   -   -   or a salt thereof, a compound of Formula XVIc:

-   -   -   or a salt thereof, a compound a compound of Formula XIVa:

-   -   -   palladium(II) acetate, cesium carbonate,            1,3-bis(dicyclohexylphosphino)propane, and toluene to form            the compound of Formula Ib or the salt thereof.

E. Method of Preparing Compounds of Formula I from Formula XI

In another embodiment, the present disclosure provides a method forpreparing a compound of Formula I:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula XI:

-   -   -   or a salt thereof, a compound of Formula VI:

-   -   -   or a salt thereof, a first base, and a first solvent to form            a compound of Formula X:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture including the compound of        Formula X or the salt thereof, a compound of PG-NH₂ or a salt        thereof, a second base, and a second solvent to form a compound        of Formula II.

-   -   -   or a salt thereof; and

    -   c) forming a third reaction mixture including the compound of        Formula II or the salt thereof, a deprotecting agent, and a        third solvent to provide the compound of Formula I or the salt        thereof,        wherein R¹, R², and R³ can each independently be hydrogen, F,        Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogen or        methyl; R⁵ can be C₃₋₆ alkyl; and PG can be an amino protecting        group.

The compound of Formula VI can be in in any suitable form. In someembodiments, the compound of Formula VI can be in a neutral form. Insome embodiments, the compound of Formula VI can be in a salt form. Insome embodiments, the compound of Formula VI can be a tosylate saltthereof.

The first base can be a tertiary amine, an aromatic amine base, anamidine-based compound, an alkali carbonate, an alkali bicarbonate, analkali phosphate tribasic, an alkali phosphate dibasic, or combinationsthereof. Suitable tertiary amines include, but are not limited to,triethylamine, tri-n-butylamine, N,N-diisopropylethylamine,N,N,N′,N′-tetramethylethylenediamine, N-methylmorpholine,N-methylpiperidine, quinuclidine, and 1,4-diazabicylo[2.2.2]-octane.Suitable aromatic amine bases include, but are not limited to, pyridine,lutidines (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine),collidines (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine,2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine),4-dimethylaminopyridine, imidazole, and1,8-bis(dimethylamino)naphthalene. Suitable amidine-based compoundsinclude, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) and 1,5-diazabicyclo-4.3.0]non-5-ene (DBN). Suitable alkalicarbonates include lithium carbonate, sodium carbonate, potassiumcarbonate, and cesium carbonate. Suitable alkali bicarbonates includelithium bicarbonate, sodium bicarbonate, and potassium bicarbonate.Suitable alkali phosphates tribasic include sodium phosphate tribasicand potassium phosphate tribasic. Suitable alkali phosphates dibasicinclude sodium phosphate dibasic and potassium phosphate dibasic. Insome embodiments, the first base can be triethylamine, tri-n-butylamine,N,N-diisopropylethylamine, N,N,N′,N′-tetramethylethylenediamine,N-methylmorpholine, N-methylpiperidine, 1,4-diazabicylo[2.2.2]-octane,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo-4.3.0]non-5-ene,pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine,imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodiumcarbonate, sodium phosphate tribasic, sodium phosphate dibasic,potassium bicarbonate, potassium carbonate, potassium phosphatetribasic, potassium phosphate dibasic, cesium carbonate, or combinationsthereof. In some embodiments, the first base includesN,N-diisopropylethylamine. In some embodiments, the first base can beN,N-diisopropylethylamine.

The first solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the first solvent can be ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethylether, methyl tert-butyl ether, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylenes,trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone, dimethylsulfoxide, acetonitrile, propionitrile,butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, orcombination thereof. In some embodiments, the first solvent includesisopropyl acetate and 2-methyltetrahydrofuran. In some embodiments, thefirst solvent can be isopropyl acetate and 2-methyltetrahydrofuran.

The compound of PG-NH₂ can be in any suitable form. In some embodiments,the compound of PG-NH₂ can be in a neutral form. In some embodiments,the compound of PG-NH₂ can be in a salt form. In some embodiments, thecompound of PG-NH₂ can be a hemisulfate, a sulfate, a chloride, abromide, a carbonate, a nitrate, or an acetate salt thereof.

PG can be an amino protecting group. Suitable amino protecting groupsinclude, but are not limited to, a carbobenzyloxy (Cbz) group, ap-methoxybenzyl carbonyl (Moz or MeOZ) group, a tert-Butyloxycarbonyl(BOC) group, a 2-trimethylsilylethyoxymethyl (SEM) group, a9-fluorenylmethyloxycarbonyl (Fmoc) group, an acetyl (Ac) group, abenzoyl (Bz) group, a benzyl (Bn) group, a carbamate group, ap-methoxybenzyl (PMB) group, a 2,4-dimethoxybenzyl group (DMB), a1-(2,4-dimethoxyphenyl)ethyl, a 3,4-dimethoxybenzyl (DMPB) group, ap-methoxyphenyl (PMP) group, a tosyl (Ts) group, a Troc (trichloroethylchloroformate) group, and other sulfonamides (Nosyl & Nps) groups. Insome embodiments, PG can be 2,4-dimethoxybenzyl.

In some embodiments, the compound of PG-NH₂ can be2,4-dimethoxybenzylamine.

The second base can be a tertiary amine, an aromatic amine base, anamidine-based compound, an alkali carbonate, an alkali bicarbonate, analkali phosphate tribasic, an alkali phosphate dibasic, or combinationsthereof. Suitable tertiary amines include, but are not limited to,triethylamine, tri-n-butylamine, N,N-diisopropylethylamine,N,N,N′,N′-tetramethylethylenediamine, N-methylmorpholine,N-methylpiperidine, quinuclidine, and 1,4-diazabicylo[2.2.2]-octane.Suitable aromatic amine bases include, but are not limited to, pyridine,lutidines (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine),collidines (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine,2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine),4-dimethylaminopyridine, imidazole, and1,8-bis(dimethylamino)naphthalene. Suitable amidine-based compoundsinclude, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) and 1,5-diazabicyclo-4.3.0]non-5-ene (DBN). Suitable alkalicarbonates include lithium carbonate, sodium carbonate, potassiumcarbonate, and cesium carbonate. Suitable alkali bicarbonates includelithium bicarbonate, sodium bicarbonate, and potassium bicarbonate.Suitable alkali phosphates tribasic include sodium phosphate tribasicand potassium phosphate tribasic. Suitable alkali phosphates dibasicinclude sodium phosphate dibasic and potassium phosphate dibasic. Insome embodiments, the second base can be triethylamine,tri-n-butylamine, N,N-diisopropylethylamine,N,N,N′,N′-tetramethylethylenediamine, N-methylmorpholine,N-methylpiperidine, 1,4-diazabicylo[2.2.2]-octane,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo-4.3.0]non-5-ene,pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine,imidazole, 1,8-bis(dimethylamino)naphthalene, sodium bicarbonate, sodiumcarbonate, sodium phosphate tribasic, sodium phosphate dibasic,potassium bicarbonate, potassium carbonate, potassium phosphatetribasic, potassium phosphate dibasic, cesium carbonate, or combinationsthereof. In some embodiments, the second base includes potassiumcarbonate. In some embodiments, the second base can be potassiumcarbonate.

The second solvent can be any suitable polar aprotic solvent and/ornon-polar solvent. In some embodiments, the second solvent can be ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate, diethylether, methyl tert-butyl ether, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, xylenes,trifluorotoluene, N,N-dimethylformamide, N,N-dimethylacetamide,N-methyl-2-pyrrolidone, dimethylsulfoxide, acetonitrile, propionitrile,butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene, orcombinations thereof. In some embodiments, the second solvent includesisopropyl acetate and 2-methyltetrahydrofuran. In some embodiments, thesecond solvent can be isopropyl acetate and 2-methyltetrahydrofuran.

In general, the first reaction (i.e., step a)) can be performed at anambient temperature to an elevated temperature. For example, the firstreaction mixture can be at a temperature of from 20° C. to 100° C. orheated to reflux. In some embodiments, the first reaction mixture can beat a temperature of from 30° C. to 100° C., from 40° C. to 100° C., from50° C. to 100° C., from 60° C. to 90° C., from 70° C. to 90° C., orabout 80° C. In some embodiments, the first reaction mixture can be at atemperature of from 50° C. to a reflux temperature. In some embodiments,the first reaction mixture can be at a temperature of about 80° C. Insome embodiments, the first reaction mixture can be heated to reflux.

In general, the second reaction (i.e., step b)) can be performed at anambient temperature to an elevated temperature. For example, the secondreaction mixture can be at a temperature of from 20° C. to 100° C. orheated to reflux. In some embodiments, the second reaction mixture canbe at a temperature of from 30° C. to 100° C., from 40° C. to 100° C.,from 50° C. to 100° C., from 60° C. to 90° C., from 60° C. to 80° C., orabout 70° C. In some embodiments, the second reaction mixture can be ata temperature of from 50° C. to a reflux temperature. In someembodiments, the second reaction mixture can be at a temperature ofabout 70° C. In some embodiments, the second reaction mixture can beheated to reflux.

The compound of Formula II or the salt thereof can be deprotected byvarious methods known in the art to provide the compound of Formula I orthe salt thereof. When PG is 2,4-dimethoxybenzyl, the compound ofFormula II can be deprotected by various methods, for example, underacidic, reductive (hydrogenolysis), or oxidative conditions to providethe compound of Formula I or the salt thereof.

In some embodiments, the deprotecting agent can be an acid. In someembodiments, the acid can be trifluoroacetic acid, trichloroacetic acid,acetic acid, formic acid, hydrochloric acid, sulfuric acid, phosphoricacid, or combinations thereof. In some embodiments, the acid includestrifluoroacetic acid. In some embodiments, the acid can betrifluoroacetic acid.

In some embodiments, the deprotecting agent can be a hydrogen source andthe third reaction mixture further includes a transition-metal catalyst.In some embodiments, the hydrogen source can be ammonium formate, formicacid, hydrogen gas, or combinations thereof. In some embodiments, thehydrogen source includes hydrogen gas. In some embodiments, the hydrogensource includes ammonium formate. In some embodiments, the hydrogensource includes formic acid. In some embodiments, the transition-metalcatalyst can be palladium hydroxide on carbon, palladium on carbon, orplatinum oxide. In some embodiments, the transition-metal catalystincludes palladium hydroxide on carbon. In some embodiments, thetransition-metal catalyst includes palladium on carbon. In someembodiments, the transition-metal catalyst includes platinum oxide. Insome embodiments, the deprotecting agent can be hydrogen gas and thethird reaction mixture further includes palladium hydroxide on carbon,palladium on carbon, or platinum oxide. In some embodiments, thedeprotecting agent includes ammonium formate and the third reactionmixture further includes palladium hydroxide on carbon, palladium oncarbon, or platinum oxide. In some embodiments, the deprotecting agentincludes formic acid and the third reaction mixture further includespalladium hydroxide on carbon, palladium on carbon, or platinum oxide.

In some embodiments, the hydrogen source can be ammonium formate. Insome embodiments, the hydrogen source can be formic acid. In someembodiments, the transition-metal catalyst can be palladium hydroxide oncarbon. In some embodiments, the transition-metal catalyst can bepalladium on carbon. In some embodiments, the transition-metal catalystcan be platinum oxide. In some embodiments, the deprotecting agent canbe ammonium formate and the third reaction mixture further includespalladium hydroxide on carbon, palladium on carbon, or platinum oxide.In some embodiments, the deprotecting agent can be formic acid and thethird reaction mixture further includes palladium hydroxide on carbon,palladium on carbon, or platinum oxide.

In some embodiments, the deprotecting agent can be boron tribromide,2,3-dichloro-5,6-dicyano-1,4-benzoquinone, ceric ammonium nitrate, or acombination of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene.

The third solvent can be any suitable polar or non-polar, protic oraprotic solvent. In some embodiments, the third solvent can be ethylacetate, isopropyl acetate, butyl acetate, isobutyl acetate,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene,xylenes, trifluorotoluene, anisole, dimethylsulfoxide, propionitrile,butyronitrile, dichloromethane, 1,2-dichloroethane, chlorobenzene,methanol, ethanol, isopropanol, water, formic acid, acetic acid,trichloroacetic acid, or combinations thereof. In some embodiments, thethird solvent includes formic acid. In some embodiments, thedeprotecting agent can be formic acid, and the third solvent can beformic acid. In some embodiments, the third solvent includesdichloromethane. In some embodiments, the third solvent can bedichloromethane.

In general, the third reaction (i.e., step c)) can be performed at anysuitable temperature, for example, at a temperature of from −10° C. to80° C. In some embodiments, the third reaction mixture can be at atemperature of from −10° C. to 80° C., from 0° C. to 50° C., from 10° C.to 50° C., from 20° C. to 50° C., or from 20° C. to 40° C. In someembodiments, the third reaction mixture can be at a temperature of from20° C. to 40° C. In some embodiments, the third reaction mixture can beat a temperature of about 30° C. In some embodiments, the third reactionmixture can be at a temperature of about 40° C. In some embodiments, thethird solvent can be dichloromethane, and the third reaction mixture canbe heated to reflux.

In some embodiments, the method further includes d) forming a fourthreaction mixture including the salt of the compound of Formula I, athird base, and a fourth solvent to provide the compound of Formula I ina neutral form.

The third base can be an alkali carbonate or alkali hydroxide. Suitablealkali carbonates include sodium carbonate and potassium carbonate.Suitable alkali hydroxides includes sodium hydroxide and potassiumhydroxide. In some embodiments, the third base can be sodium hydroxideor potassium hydroxide. In some embodiments, the third base includessodium hydroxide. In some embodiments, the third base can be in anaqueous solution. In some embodiments, the third base includes anaqueous solution of sodium hydroxide. In some embodiments, the thirdbase can be an aqueous solution of sodium hydroxide.

The fourth solvent can be any suitable alcohol solvent, ester solvent,and/or water. In some embodiments, the fourth solvent can be methanol,ethanol, isopropanol, ethyl acetate, isopropyl acetate, water, orcombinations thereof. In some embodiments, the fourth solvent includesi) ethanol and water, or ii) ethyl acetate and water. In someembodiments, the fourth solvent includes ethanol and water. In someembodiments, the fourth solvent includes ethyl acetate and water. Insome embodiments, the fourth solvent can be i) ethanol and water, or ii)ethyl acetate and water. In some embodiments, the fourth solvent can beethanol and water. In some embodiments, the fourth solvent can be ethylacetate and water.

When the fourth solvent includes an ester solvent (e.g., ethyl acetateor isopropyl acetate), upon completion of the reaction, the reactionmixture after partition can be further treated with an aqueous solutionof sodium bicarbonate.

In general, the fourth reaction (i.e., step d)) can be performed at anysuitable temperature. For example, the fourth reaction mixture can be ata temperature of from 0° C. to 60° C. In some embodiments, the fourthreaction mixture can be at a temperature of from 0° C. to 60° C., from10° C. to 60° C., from 10° C. to 50° C., or from 20° C. to 40° C. Insome embodiments, the fourth reaction mixture can be at a temperature offrom 20° C. to 40° C. In some embodiments, the fourth reaction mixturecan be at a temperature of about 20° C. In some embodiments, the fourthreaction mixture can be at a temperature of about 40° C.

In some embodiments of any one of formulae I, II, X, and XI, R² can beCl, F, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; and R¹ and R³ can eachindependently be hydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy.The C₁₋₃ alkyl can be methyl, ethyl, n-propyl, or isopropyl. The C₁₋₃alkoxy can be methoxy, ethoxy, n-propoxy, or isopropoxy. In someembodiments of any one of formulae I, II, X, and XI, R² can be Cl, F,CN, CF₃, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy,or isopropoxy; and R¹ and R³ can each independently be hydrogen, F, Cl,CN, CF₃, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy,or isopropoxy. In some embodiments of any one of formulae I, II, X, andXI, R² can be Cl, F, CN, CF₃, methyl, ethyl, n-propyl, isopropyl,methoxy, ethoxy, n-propoxy, or isopropoxy; and R¹ and R³ can each behydrogen. In some embodiments of any one of formulae I, II, X, and XI,R² can be F, and R¹ and R³ can each be hydrogen.

In some embodiments of any one of formulae I, II, VI, and X, R⁴ can behydrogen. In some embodiments of any one of formulae I, II, VI, and X,R⁴ can be methyl.

In some embodiments of any one of formulae I, II, VI, and X, R⁵ can beC₃₋₆ alkyl. In some embodiments, R⁵ can be n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl. In someembodiments of any one of formulae I, II, VI, and X, R⁵ can be n-butyl.

In some embodiments of any one of formulae I, II, VI, and X, R⁴ can bemethyl; and R⁵ can be C₃₋₆ alkyl. In some embodiments of any one offormulae I, II, VI, and X, R⁴ can be methyl; and R⁵ can be n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, or hexyl. In some embodiments of any one of formulae I, II,VI, and X, R⁴ can be methyl; and R⁵ can be n-butyl.

In some embodiments, the compound of Formula I can be of Formula Ia:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula I can be of Formula Ib:

or a salt thereof.

In some embodiments, the compound of Formula XI can be of Formula XIa:

or a salt thereof, wherein R² is defined and described herein.

In some embodiments, the compound of Formula XI can be of Formula Xb:

or a salt thereof.

In some embodiments, the compound of Formula VI can be of Formula VIa:

wherein R⁵ is defined and described herein.

In some embodiments, the compound of Formula VI can be of Formula VIb:

In some embodiments, the compound of Formula X can be of Formula IXa:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula X can be of Formula IXb:

or a salt thereof.

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula Ib:

or a salt thereof, the method including:

-   -   a) forming a first reaction mixture including a compound of        Formula XIb:

-   -   -   or the salt thereof, a compound of Formula VIb:

-   -   -   N,N-diisopropylethylamine, 2-methyltetrahydrofuran, and            isopropyl acetate to form a compound of Formula Xb:

-   -   -   or a salt thereof;

    -   b) forming a second reaction mixture including the compound of        Formula Xb or the salt thereof, 2,4-dimethoxybenzylamine,        potassium carbonate, 2-methyltetrahydrofuran, and isopropyl        acetate to form a compound of Formula IIb:

-   -   -   or a salt thereof; and

    -   c) forming a third reaction mixture including the compound of        Formula IIb or the salt thereof, trifluoroacetic acid, and        dichloromethane to prepare a trifluoroacetic acid salt of the        compound of Formula Ib:

and

-   -   d) forming a fourth reaction mixture including the        trifluoroacetic acid salt of the compound of Formula Ib, sodium        hydroxide, ethanol, and water to provide the compound of Formula        Ib in a salt-free form.

In some embodiments, the compound of Formula Xb or the salt thereof canbe isolated in a solution including 2-methyltetrahydrofuran andisopropyl acetate and used in the following step b) without purificationand/or removal of the 2-methyltetrahydrofuran and isopropyl acetate. Insome embodiments, the compound of Formula Xb or the salt thereof can beisolated in a solution including 2-methyltetrahydrofuran and isopropylacetate and used in the following step b) without removal of the2-methyltetrahydrofuran and isopropyl acetate. In some embodiments, thecompound of Formula Xb or the salt thereof can be isolated in a solid byprecipitation upon addition of n-heptane to a solution including2-methyltetrahydrofuran and isopropyl acetate. In some embodiments, thecompound of Formula Xb or the salt thereof can be isolated in a solid byprecipitation upon addition of n-heptane to a solution including2-methyltetrahydrofuran and isopropyl acetate and used in the followingstep b) without purification.

F. Methods of Preparing Intermediates

The intermediates used in the methods of the present disclosure can beprepared by a variety of methods.

1. Preparation of a Salt of (R)-2-Amino-2-methylhexan-1-ol, Route 1

In some embodiments, the present disclosure provides a method forpreparing a salt of (R)-2-amino-2-methylhexan-1-ol:

the method including:

-   -   1) forming a first reaction mixture including C₁₋₄ alkyl        alaninate having the formula:

-   -   -   or a salt thereof, an aldehyde, a first base, a desiccant,            and a first solvent to form an imine of C₁₋₄ alkyl alaninate            having the formula:

-   -   2a) forming a second mixture including the imine of C₁₋₄ alkyl        alaninate, an electorophile, a second base, and a second solvent        to form an imine of C₁₋₄ alkyl 2-amino-2-methylhexanoate having        the formula:

-   -   2b) forming a third reaction mixture including the imine of C₁₋₄        alkyl 2-amino-2-methylhexanoate, a first acid and a third        solvent to form a first salt of C₁₋₄ alkyl        2-amino-2-methylhexanoate:

-   -   2c) forming a fourth reaction mixture including the first salt        of C₁₋₄ alkyl 2-amino-2-methylhexanoate, a third base, a fourth        solvent, and water to form C₁₋₄ alkyl 2-amino-2-methylhexanoate        in a neutral form;    -   3) forming a fifth reaction mixture including C₁₋₄ alkyl        2-amino-2-methylhexanoate, a second acid, and a fifth solvent to        form a second salt of C₁₋₄ alkyl 2-amino-2-methylhexanoate;    -   4) forming a sixth reaction mixture including the second salt of        C₁₋₄ alkyl 2-amino-2-methylhexanoate, an enzyme, a fourth base,        and a sixth solvent to provide C₁₋₄ alkyl        (R)-2-amino-2-methylhexanoate:

-   -   -   or a salt thereof;

    -   5) forming a seventh reaction mixture including C₁₋₄ alkyl        (R)-2-amino-2-methylhexanoate or the salt thereof, a BOC        protecting reagent, and a seventh solvent to form C₁₋₄ alkyl        (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate:

-   -   6) forming an eighth reaction mixture including C₁₋₄ alkyl        (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, a        reductant, a promoter, and an eighth solvent to form tert-butyl        (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate:

and

-   -   7) forming a ninth reaction mixture including tert-butyl        (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, a third acid, and a        ninth solvent to provide the salt of        (R)-2-amino-2-methylhexan-1-ol,        wherein R can be unsubstituted or substituted aryl or        unsubstituted or substituted aryl-CH═CH—.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can beprepared according to steps 1-7 as shown in the scheme of FIG. 3A.

In some embodiments, C₁₋₄ alkyl in any one of formulae or compounds insteps 1, 2a, 2b, 2c, and 3-6 can be methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, or tert-butyl. In some embodiments, C₁₋₄ alkyl inany one of formulae or compounds in steps 1, 2a, 2b, 2c, and 3-6 can beisopropyl.

With respect to step 1, C₁₋₄ alkyl alaninate or the salt thereof, thealdehyde, the first base, the desiccant, the first solvent, the imine ofC₁₋₄ alkyl alaninate, and reaction temperature are described herein.

In some embodiments, C₁₋₄ alkyl alaninate can be C₁₋₄ alkyl L-alaninate,C₁₋₄ alkyl D-alaninate, or a mixture thereof. In some embodiments, C₁₋₄alkyl alaninate can be methyl alaninate, ethyl alaninate, n-propylalaninate, isopropyl alaninate, n-butyl alaninate, sec-butyl alaninate,or tert-butyl alaninate. In some embodiments, C₁₋₄ alkyl alaninate canbe isopropyl alaninate. In some embodiments, C₁₋₄ alkyl alaninate can beisopropyl L-alaninate. Isopropyl L-alaninate can be in any suitableform, for example, in a neutral form or a salt form. In someembodiments, isopropyl L-alaninate can be a HCl salt thereof.

The aldehyde can be any suitable aldehyde capable of forming an iminewith an amine. For example, the aldehyde can be benzaldehyde,2-chlorobenzaldehyde, 4-chlorobenzaldehyde, 3-hydroxybenzaldehyde,4-hydroxybenzaldehyde, 3-phenylprop-2-enal,3-(4-methylphenyl)prop-2-enal,3-(4-hydroxy-3-methyoxyphenyl)prop-2-enal, 2-methylbenzaldehyde,4-methylbenzaldehyde, or 4-methoxybenzaldehyde. In some embodiments, thealdehyde can be benzaldehyde.

The first base can be a tertiary amine (e.g., trimethylamine,triethylamine, N,N-diisopropylethylamine, N-methylpiperidine, ortri-n-butylamine), a carboxylate (e.g., sodium acetate or potassiumacetate), or an inorganic base (e.g., sodium carbonate, potassiumcarbonate; cesium carbonate, sodium bicarbonate, potassium bicarbonate,sodium phosphate tribasic, or potassium phosphate tribasic). In someembodiments, the first base includes trimethylamine. In someembodiments, the first base can be trimethylamine.

The desiccant can be any suitable agent or method capable of removingwater formed from the condensation. For example, the desiccant can besodium sulfate, magnesium sulfate, a trialkyl orthoformate (e.g.,trimethyl orthoformate), molecular sieves, or an azeotropic removal ofwater (e.g., using a Dean-Stark trap). In some embodiments, thedesiccant includes sodium sulfate. In some embodiments, the desiccantcan be sodium sulfate.

The first solvent can be an aromatic solvent (e.g., toluene, xylenes,chlorobenzene, fluorobenzene, or trifluorotoluene), an ether (e.g.,diethyl ether, methyl tert-butyl ether, tetrahydrofuran,2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g.,dichloromethane or 1,2-dichloroethane), an ester (e.g., ethyl acetate,butyl acetate, or isobutyl acetate), an alcohol (e.g., methanol,ethanol, or isopropanol), or combinations thereof. In some embodiments,the first solvent includes toluene. In some embodiments, the firstsolvent can be toluene.

In some embodiments, the imine of C₁₋₄ alkyl alaninate has the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be phenyl. In some embodiments, the imine of C₁₋₄ alkyl alaninatecan be an imine of isopropyl alaninate having the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be phenyl. In some embodiments, the imine of isopropyl alaninatecan be isopropyl 2-(benzylideneamino)propanoate:

The imine of isopropyl alaninate can be isolated in a solution of thefirst solvent that can be used in the condensation reaction. In someembodiments, isopropyl 2-(benzylideneamino)propanoate can be isolated asa solution in toluene and used directly in the following step withoutpurification and/or removal of the solvent.

In general, the condensation reaction (i.e., step 1) can be performed atany suitable temperature. For example, the condensation reaction mixturecan be at a temperature of from 0° C. to 80° C. In some embodiments, thecondensation reaction mixture can be at a temperature of from 20° C. to30° C.

Step 2 includes three steps as described in steps 2a, 2b, and 2c.

With respect to step 2a, the imine of C₁₋₄ alkyl alaninate, theelectorophile, the second base, the second solvent, the imine of C₁₋₄alkyl 2-amino-2-methylhexanoate, and reaction temperature are describedherein.

In some embodiments, the imine of C₁₋₄ alkyl alaninate can be an imineof isopropyl alaninate. In some embodiments, the imine of isopropylalaninate can be isopropyl 2-(benzylideneamino)propanoate. In someembodiments, the imine of isopropyl alaninate can be a solution ofisopropyl 2-(benzylideneamino)propanoate in toluene.

In some embodiments, the electorophile can be n-butyl bromide, n-butyliodide, n-butyl methanesulphonate, n-butyl 4-methylbenzenesulfonate, orn-butyl sulfate. In some embodiments, the electorophile can be n-butylbromide.

The second base can be an alkali alkoxide (e.g., sodium isopropoxide,sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, orpotassium isopropoxide), an alkali hydroxide in the presence of a phasetransfer catalyst (e.g., sodium hydroxide or potassium hydroxide incombination with tetra-n-butylammonium bromide or tetra-n-butylammoniumhydroxide), an alkali amide (e.g., lithium diisopropylamide, lithiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)-amide, orlithium 2,2,6,6,-tetramethylpiperidide), an alkali carbonate (e.g.,sodium carbonate, potassium carbonate, or cesium carbonate), or sodiumhydride. In some embodiments, the second base includes sodiumisopropoxide. In some embodiments, the second base can be sodiumisopropoxide.

The second solvent can be an aromatic solvent (e.g., toluene, xylenes,chlorobenzene, or fluorobenzene), an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or1,4-dioxane), a polar aprotic solvent (e.g., dimethylsulfoxide,N-methyl-2-pyrrolidone, or sulfolane), an alcohol (e.g., isopropanol,tert-butanol, or 2-methylbutan-2-ol), a chlorinated solvent (e.g.,dichloromethane, or chlorobenzene), or combinations thereof. In someembodiments, the second solvent includes tetrahydrofuran and toluene. Insome embodiments, the second solvent can be tetrahydrofuran and toluene.

In some embodiments, the imine of C₁₋₄ alkyl 2-amino-2-methylhexanoatehas the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be phenyl. In some embodiments, the imine of C₁₋₄ alkyl2-amino-2-methylhexanoate can be an imine of isopropyl2-amino-2-methylhexanoate having the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be phenyl. In some embodiments, the imine of isopropyl2-amino-2-methylhexanoate can be isopropyl2-(benzylideneamino)-2-methylhexanoate:

The second reaction mixture upon completion can be directly used in thefollowing step without removal of the second solvent. In someembodiments, upon completion of the alkylation reaction, the secondreaction mixture including isopropyl2-(benzylideneamino)-2-methylhexanoate, tetrahydrofuran, and toluene canbe directly used in the following step without removal of the solvent.

In general, the alkylation reaction (i.e., step 2a) can be performed atany suitable temperature, for example, at a temperature of from 0° C. to80° C. In some embodiments, the reaction mixture of the alkylationreaction can be at a temperature of from 40° C. to 50° C.

With respect to step 2b, the imine of C₁₋₄ alkyl2-amino-2-methylhexanoate, the first acid, the third solvent, the firstsalt of C₁₋₄ alkyl 2-amino-2-methylhexanoate, and reaction temperatureare described herein.

In some embodiments, the imine can be an imine of isopropyl2-amino-2-methylhexanoate. In some embodiments, the imine can beisopropyl 2-(benzylideneamino)-2-methylhexanoate. In some embodiments,the imine can be the reaction mixture from step 2a including isopropyl2-(benzylideneamino)-2-methylhexanoate, tetrahydrofuran, and toluene.

The first acid can be a mineral acid (e.g., sulfuric acid, hydrochloricacid or phosphoric acid) or an organic acid (e.g., methanesulfonic acid,fumaric acid, acetic acid, formic acid, or ascorbic acid). In someembodiments, the first acid includes sulfuric acid. In some embodiments,the first acid can be in an aqueous solution. In some embodiments, thefirst acid includes an aqueous solution of sulfuric acid. In someembodiments, the first acid can be an aqueous solution of sulfuric acid.

In some embodiments, the first salt of C₄ alkyl2-amino-2-methylhexanoate can be a first salt of isopropyl2-amino-2-methylhexanoate. In some embodiments, the first salt ofisopropyl 2-amino-2-methylhexanoate can be a sulfuric acid salt thereof.

The third solvent can be an aromatic solvent (e.g., toluene, xylenes,chlorobenzene, or fluorobenzene), an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or1,4-dioxane), a polar aprotic solvent (e.g., dimethylsulfoxide,N-methyl-2-pyrrolidone, or sulfolane), an alcohol (e.g., isopropanol,tert-butanol, or 2-methylbutan-2-ol), a chlorinated solvent (e.g.,dichloromethane, or chlorobenzene), water, or combinations thereof. Insome embodiments, the third solvent includes tetrahydrofuran, toluene,and water. In those embodiments, the third reaction mixture can be abiphasic reaction mixture. In some embodiments, the third solvent can betetrahydrofuran, toluene, and water.

In some embodiments, the first salt of isopropyl2-amino-2-methylhexanoate can be isolated in an aqueous solution andused directly in the following step without purification and/or removalof water. In some embodiments, the sulfuric acid salt of isopropyl2-amino-2-methylhexanoate can be isolated in an aqueous solution andused directly in the following step without purification and removal ofwater.

In general, the hydrolysis reaction (i.e., step 2b) can be performed atany suitable temperature, for example, at a temperature of from 0° C. to80° C. In some embodiments, the reaction mixture of the hydrolysisreaction can be at a temperature of from 20° C. to 30° C.

Steps 2a and 2b can be performed in an one-pot reaction, in which thesecond reaction mixture upon completion can be directly treated with anaqueous solution of the first acid to form the third reaction mixture.

With respect to step 2c, the first salt of C₁₋₄ alkyl2-amino-2-methylhexanoate, the third base, the fourth solvent, C₁₋₄alkyl 2-amino-2-methylhexanoate, and reaction temperature are describedherein.

In some embodiments, the first salt of C₁₋₄ alkyl2-amino-2-methylhexanoate can be a first salt of isopropyl2-amino-2-methylhexanoate. In some embodiments, the first salt ofisopropyl 2-amino-2-methylhexanoate can be the sulfuric acid saltthereof. In some embodiments, the first salt of isopropyl2-amino-2-methylhexanoate can be the aqueous solution of the sulfuricacid salt thereof.

The third base can be an inorganic base (e.g., lithium hydroxide, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium bicarbonate, potassium bicarbonate, sodium phosphate tribasic, orpotassium phosphate tribasic) or an organic base (e.g., sodium acetate,potassium acetate, sodium methoxide, sodium tert-butoxide, or potassiumtert-butoxide). In some embodiments, the third base can be in an aqueoussolution. In some embodiments, the third base includes an aqueoussolution of sodium hydroxide. In some embodiments, the third base can bean aqueous solution of sodium hydroxide.

The fourth solvent can be an aromatic solvent (e.g., toluene, xylenes,or trifluorotoluene); an ether (e.g., diethyl ether, methyl tert-butylether, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-dioxane), achlorinated solvent (e.g., dichloromethane or 1,2-dichloroethane), orcombinations thereof. In some embodiments, the fourth solvent includes2-methyltetrahydrofuran. In some embodiments, the neutralizationreaction (i.e., step 2c) can be performed by extraction. In someembodiments, the fourth solvent can be 2-methyltetrahydrofuran.

In some embodiments, C₁₋₄ alkyl 2-amino-2-methylhexanoate can beisopropyl 2-amino-2-methylhexanoate. In some embodiments, isopropyl2-amino-2-methylhexanoate can be isolated as a solution in the fourthsolvent. In some embodiments, isopropyl 2-amino-2-methylhexanoate can beisolated as a solution in 2-methyltetrahydrofuran and used directly inthe following step without purification and/or removal of the solvent.

In general, the neutralization reaction (i.e., step 2c) can be performedat any suitable temperature, for example, at a temperature of from 0° C.to 40° C. In some embodiments, the reaction mixture of theneutralization reaction can be at a temperature of from 20° C. to 30° C.

With respect to step 3, C₁₋₄ alkyl 2-amino-2-methylhexanoate, the secondacid, the fifth solvent, the second salt of C₁₋₄ alkyl2-amino-2-methylhexanoate, and reaction temperature are describedherein.

In some embodiments, C₁₋₄ alkyl 2-amino-2-methylhexanoate can beisopropyl 2-amino-2-methylhexanoate. In some embodiments, the isopropyl2-amino-2-methylhexanoate can be the solution thereof in2-methyltetrahydrofuran.

The second acid can be phosphoric acid, sulfuric acid, 4-nitrobenzoicacid, fumaric acid, succinic acid, or tartaric acid. In someembodiments, the second acid includes phosphoric acid. In someembodiments, the second acid can be in an aqueous solution. In someembodiments, the second acid includes an aqueous solution of phosphoricacid. In some embodiments, the second acid can be an aqueous solution ofphosphoric acid.

The fifth solvent can be an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or1,4-dioxane), a ketone (e.g., acetone or methyl isobutyl ketone), analcohol (e.g., ethanol or isopropanol), an ester (e.g., ethyl acetate,butyl acetate, or isobutyl acetate), a hydrocarbon (e.g., n-heptane,hexanes, cyclohexane, methylcyclohexane), water, or combinationsthereof. In some embodiments, the fifth solvent includes2-methyltetrahydrofuran and water. In some embodiments, the fifthsolvent can be 2-methyltetrahydrofuran and water.

In some embodiments, the second salt of C₁₋₄ alkyl2-amino-2-methylhexanoate can be a second salt of isopropyl2-amino-2-methylhexanoate. In some embodiments, the second salt ofisopropyl 2-amino-2-methylhexanoate can be a phosphate salt thereof. Insome embodiments, the phosphate salt of isopropyl2-amino-2-methylhexanoate can be used directly without purification.

In general, the salt formation reaction (i.e., step 3) can be performedat any suitable temperature, for example, at a temperature of from 0° C.to 40° C. In some embodiments, the reaction mixture of the saltformation can be at a temperature of from 20° C. to 30° C.

With respect to step 4, the second salt of C₁₋₄ alkyl2-amino-2-methylhexanoate, the enzyme, the fourth base, the sixthsolvent, C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate or the salt thereof,and reaction temperature are described herein.

In some embodiments, the second salt of C₁₋₄ alkyl2-amino-2-methylhexanoate can be a second salt of isopropyl2-amino-2-methylhexanoate. In some embodiments, the second salt ofisopropyl 2-amino-2-methylhexanoate can be the phosphate salt thereof.

The enzyme of step 4) can be a serine endopeptidase subtilisin A (e.g.,Alcalase® or other formulations thereof), or other proteases andhydrolases (e.g., protease from Aspergillus oryzae, amano lipase A fromAspergillus niger, or lipase from Candida lipolytica). In someembodiments, the enzyme includes a serine endopeptidase subtilisin A. Insome embodiments, the enzyme includes Alcalase®. In some embodiments,the enzyme can be a serine endopeptidase subtilisin A. In someembodiments, the enzyme can be Alcalase®.

The fourth base can be an inorganic base (e.g., sodium phosphatetribasic, potassium phosphate tribasic, sodium phosphate dibasic,potassium phosphate dibasic, sodium carbonate, potassium carbonate,sodium bicarbonate, or potassium bicarbonate) or an organic base (e.g.,sodium acetate or potassium acetate). In some embodiments, the fourthbase includes potassium phosphate tribasic. In some embodiments, thefourth base can be in an aqueous solution. In some embodiments, thefourth base includes an aqueous solution of potassium phosphatetribasic. In some embodiments, the fourth base can be an aqueoussolution of potassium phosphate tribasic.

The sixth solvent can be a mixture of water and a water-miscible organicco-solvent (e.g., acetone, dimethylsulfoxide, acetonitrile, ortert-butanol), a mixture of water and a water-immiscible organicco-solvent (e.g., methyl tert-butyl ether, ethyl acetate, or methylisobutyl ketone). In some embodiments, the sixth solvent includesacetone and water. In some embodiments, the sixth solvent can be acetoneand water.

In some embodiments, C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate can beisopropyl (R)-2-amino-2-methylhexanoate. Isopropyl(R)-2-amino-2-methylhexanoate can be isolated in a solution of thewater-immiscible organic co-solvent that can be used in the sixthreaction mixture. In some embodiments, isopropyl(R)-2-amino-2-methylhexanoate can be isolated as a solution in methyltert-butyl ether and used directly in the following step withoutpurification and/or removal of the solvent.

In general, the enzymatic resolution reaction (i.e., step 4) can beperformed at any suitable temperature, for example, at a temperature offrom 0° C. to 50° C. In some embodiments, the reaction mixture of theenzymatic resolution reaction can be at a temperature of from 30° C. to40° C.

With respect to step 5, C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate or thesalt thereof, the BOC protecting reagent, the seventh solvent, C₁₋₄alkyl (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, and reactiontemperature are described herein.

In some embodiments, C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate can beisopropyl (R)-2-amino-2-methylhexanoate. In some embodiments, isopropyl(R)-2-amino-2-methylhexanoate can be the solution thereof in methyltert-butyl ether.

In some embodiments, the BOC protecting reagent can be di-tert-butyldicarbonate, di-tert-butyl-iminodicarboxylate, or tert-butylchloroformate. In some embodiments, the BOC protecting reagent includesdi-tert-butyl dicarbonate. In some embodiments, the BOC protectingreagent can be di-tert-butyl dicarbonate.

The seventh solvent can be an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or1,4-dioxane), a ketone (e.g., acetone or methyl isobutyl ketone, etc.),an ester (e.g., ethyl acetate, butyl acetate, or isobutyl acetate), anaromatic solvent (e.g., toluene or xylenes), a chlorinated solvent(e.g., dichloromethane or 1,2-dichloroethane), water, or combinationsthereof. In some embodiments, the seventh solvent includes methyltert-butyl ether. In some embodiments, the seventh solvent can be methyltert-butyl ether.

In some embodiments, C₁₋₄ alkyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isolated inthe seventh solvent. In some embodiments, isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isolated asa solution in methyl tert-butyl ether and used directly in the followingstep without purification and/or removal of methyl tert-butyl ether.

In general, the BOC-protecting reaction (i.e., step 5) can be performedat any suitable temperature, for example, at a temperature of from 0° C.to 100° C. In some embodiments, the reaction mixture of theBOC-protecting reaction can be at a temperature of from 20° C. to 30° C.

With respect to step 6, C₁₋₄ alkyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, the reductant, thepromoter, the eighth solvent, isolation of tert-butyl(R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, and reaction temperatureare described herein.

In some embodiments, C₁₋₄ alkyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. In someembodiments, isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be the solutionthereof in methyl tert-butyl ether.

The reductant can be any suitable reducing agent capable of reducing anester group (e.g., isopropyl ester) to the corresponding —CH₂OH. Forexample, the reductant can be a borohydride reagent (e.g., lithiumborohydride, potassium borohydride, lithium triethylborohydride, orsodium borohydride/iodine), an aluminum hydride reagent (e.g., lithiumaluminum hydride or diisobutylaluminum hydride). In some embodiments,the reductant includes lithium borohydride. In some embodiments, thereductant includes a solution of lithium borohydride in tetrahydrofuran.In some embodiments, the reductant can be lithium borohydride. In someembodiments, the reductant can be a solution of lithium borohydride intetrahydrofuran.

The promoter can be an alcohol (e.g., methanol, ethanol, n-propanol,isopropanol, or tert-butanol). In some embodiments, the promoterincludes methanol. In some embodiments, the promoter can be methanol.

The eighth solvent can be an ether (diethyl ether, methyl tert-butylether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, or1,2-dimethoxyethane, etc.), an aromatic solvent (e.g., toluene orxylenes), or combinations thereof. In some embodiments, the eighthsolvent includes methyl tert-butyl ether and tetrahydrofuran. In someembodiments, the eighth solvent can be methyl tert-butyl ether andtetrahydrofuran.

tert-Butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate can be isolatedin the eighth solvent. In some embodiments, tert-butyl(R)-(1-hydroxy-2-methylhexan-2-yl)carbamate can be isolated as asolution in methyl tert-butyl ether and used directly in the followingstep without purification and/or removal of methyl tert-butyl ether.

In general, the reduction reaction (i.e., step 6) can be performed atany suitable temperature, for example, at a temperature of from 0° C. to60° C. In some embodiments, the reaction mixture of the reductionreaction can be at a temperature of from 20° C. to 30° C.

With respect to step 7, the tert-butyl(R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, the third acid, the ninthsolvent, the salt of (R)-2-amino-2-methylhexan-1-ol, and reactiontemperature are described herein.

In some embodiments, the tert-butyl(R)-(1-hydroxy-2-methylhexan-2-yl)carbamate can be the solution thereofin methyl tert-butyl ether.

The third acid can be a sulfonic acid (e.g., p-toluenesulfonic acid,methanesulfonic acid, or benzenesulfonic acid), a mineral acid (e.g.,hydrochloric acid or sulfuric acid), or an organic acid (e.g.,trifluoroacetic acid). In some embodiments, the third acid includesp-toluenesulfonic acid. In some embodiments, the third acid can bep-toluenesulfonic acid.

The ninth solvent can be an alcohol (e.g., methanol, ethanol,n-propanol, isopropanol, or n-butanol), an ether (e.g., diethyl ether,methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, or 1,2 dimethoxyethane), an aromatic solvent (e.g., tolueneor xylenes), a chlorinated solvent (e.g., dichloromethane or1,2-dichloroethane), a ketone solvent (e.g., acetone or methyl isobutylketone), an ester (e.g., ethyl acetate, butyl acetate, or isobutylacetate), or combinations thereof. In some embodiments, the ninthsolvent includes isopropanol. In some embodiments, the ninth solvent canbe isopropanol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can be acompound of Formula VIb:

In general, the BOC-deprotecting reaction (i.e., step 7) can beperformed at any suitable temperature, for example, at a temperature offrom 0° C. to 100° C. In some embodiments, the reaction mixture of theBOC-deprotecting reaction can be at a temperature of from 40° C. to 60°C.

2. Preparation of a Salt of (R)-2-Amino-2-methylhexan-1-ol, Route 2

In some embodiments, the above steps 3, 4, and 5 can be replaced withsteps 8 and 9 as shown in the scheme of FIG. 3B to provide theBoc-protected isopropyl (R)-2-amino-2-methylhexanoate.

In some embodiments, the present disclosure provides a method forpreparing a salt of (R)-2-amino-2-methylhexan-1-ol:

the method including:

-   -   1) forming a first reaction mixture including C₁₋₄ alkyl        alaninate:

-   -   or a salt thereof, an aldehyde, a first base, a desiccant, and a        first solvent to form an imine of C₁₋₄ alkyl alaninate having        the formula:

-   -   2a) forming a second mixture including the imine of C₁₋₄ alkyl        alaninate, an electrophile, a second base, and a second solvent        to form an imine of C₁₋₄ alkyl 2-amino-2-methylhexanoate having        the formula:

-   -   2b) forming a third reaction mixture including the imine of C₁₋₄        alkyl 2-amino-2-methylhexanoate, a first acid and a third        solvent to form a salt of C₁₋₄ alkyl 2-amino-2-methylhexanoate:

-   -   2c) forming a fourth reaction mixture including the salt of C₁₋₄        alkyl 2-amino-2-methylhexanoate, a third base, a fourth solvent,        and water to form C₁₋₄ alkyl 2-amino-2-methylhexanoate in a        neutral form;    -   8) forming a fifth reaction mixture including C₁₋₄ alkyl        2-amino-2-methylhexanoate, a second acid, and a fifth solvent to        form a first salt of C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate:

9) forming a sixth reaction mixture including the first salt of C₁₋₄alkyl (R)-2-amino-2-methylhexanoate, a BOC-protecting reagent, a fourthbase, and a sixth solvent to form C₁₋₄ alkyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate:

-   -   6) forming an eighth reaction mixture including C₁₋₄ alkyl        (R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, a        reductant, a promoter, and an eighth solvent to form tert-butyl        (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate:

and

-   -   7) forming a ninth reaction mixture including tert-butyl        (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate, a third acid, and a        ninth solvent to provide the salt of        (R)-2-amino-2-methylhexan-1-ol,        wherein R can be unsubstituted or substituted aryl or        unsubstituted or substituted aryl-CH═CH—.

In some embodiments, C₁₋₄ alkyl in any one of formulae or compounds insteps 1, 2a, 2b, 2c, 8-9, and 6 can be methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, C₁₋₄alkyl in any one of formulae or compounds in steps 1, 2a, 2b, 2c, 8-9,and 6 can be isopropyl.

Steps 1, 2a, 2b, 3c, 6, and 7 are described above in the preparation ofthe salt of (R)-2-amino-2-methylhexan-1-ol, Route 1.

With respect to step 8, C₁₋₄ alkyl 2-amino-2-methylhexanoate, the secondacid, the fifth solvent, the first salt of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate, and reaction temperature are describedherein.

In some embodiments, C₁₋₄ alkyl 2-amino-2-methylhexanoate can beisopropyl 2-amino-2-methylhexanoate. In some embodiments, isopropyl2-amino-2-methylhexanoate can be the solution thereof in2-methyltetrahydrofuran.

The second acid can be an amino acid (e.g., N-acetyl-L-leucine,N-acetyl-L-aspartic acid, or N-acetyl-L-phenylalanine), a tartaric acidor a derivative thereof (e.g., dibenzoyl-D-tartaric acid,di-p-toluoyl-D-tartaric acid, L-mandelic acid, or O-acetyl-D-mandelicacid). In some embodiments, the second acid includes N-acetyl-L-leucine.In some embodiments, the second acid can be N-acetyl-L-leucine.

The fifth solvent can be an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane,or 1,2 dimethoxyethane), a ketone (e.g., acetone or methyl isobutylketone), an alcohol (e.g., methanol, ethanol, n-propanol, orisopropanol), an ester (e.g., ethyl acetate, butyl acetate, or isobutylacetate), a hydrocarbon solvent (e.g., hexanes, n-heptane, cyclohexane,or methylcyclohexane), or combinations thereof. In some embodiments, thefifth solvent includes 2-methyltetrahydrofuran. In some embodiments, thefifth solvent can be 2-methyltetrahydrofuran.

In some embodiments, the first salt of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate can be a first salt of isopropyl(R)-2-amino-2-methylhexanoate. In some embodiments, the first salt ofC₁₋₄ alkyl (R)-2-amino-2-methylhexanoate can be a N-acetyl-L-leucinesalt of the formula:

In some embodiments, the first salt of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate can be a N-acetyl-L-leucine salt of theformula:

The first salt of isopropyl (R)-2-amino-2-methylhexanoate can be useddirectly in the following step 9 without purification. In someembodiments, the N-acetyl-L-leucine salt of isopropyl(R)-2-amino-2-methylhexanoate can be used directly in the following step9 without purification.

In general, the salt formation and resolution reaction (i.e., step 8)can be performed at any suitable temperature, for example, at atemperature of from 0° C. to 80° C. In some embodiments, the reactionmixture of the salt formation and resolution reaction can be at atemperature of from 20° C. to 50° C.

With respect to step 9, the first salt of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate, the BOC-protecting reagent, the fourthbase, the sixth solvent, C₁₋₄ alkyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate, and reactiontemperature are described herein.

In some embodiments, the first salt of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate can be a first salt of isopropyl(R)-2-amino-2-methylhexanoate. In some embodiments, the first salt ofisopropyl (R)-2-amino-2-methylhexanoate can be the N-acetyl-L-leucinesalt.

In some embodiments, the BOC protecting reagent can be di-tert-butyldicarbonate, di-tert-butyl-iminodicarboxylate, or tert-butylchloroformate. In some embodiments, the BOC protecting reagent includesdi-tert-butyl dicarbonate. In some embodiments, the BOC protectingreagent can be di-tert-butyl dicarbonate.

The sixth solvent can be an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane,or 1,2-dimethoxyethane), a ketone (e.g., acetone or methyl isobutylketone), an ester (e.g., ethyl acetate, butyl acetate, or isobutylacetate), an aromatic solvent (e.g., toluene or xylenes), a chlorinatedsolvent (e.g., dichloromethane or 1,2-dichloroethane), an alcohol (e.g.,ethanol, n-butanol, or 2 propanol), water, or combinations thereof. Insome embodiments, the sixth solvent includes water. In some embodiments,the sixth solvent can be water.

In some embodiments, C₁₋₄ alkyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate. In someembodiments, isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isolated inthe fifth solvent. In some embodiments, isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate can be isolated asa solution in methyl tert-butyl ether and used directly in the followingstep without purification and/or removal of methyl tert-butyl ether.

In general, the BOC-protection reaction (i.e., step 9) can be performedat any suitable temperature, for example, at a temperature of from 0° C.to 100° C. In some embodiments, the reaction mixture of theBOC-protecting reaction can be at a temperature of from 20° C. to 30° C.

3. Preparation of a Salt of (R)-2-Amino-2-methylhexan-1-ol, Route 3

In some embodiments, the present disclosure provides a method forpreparing a salt of (R)-2-amino-2-methylhexan-1-ol:

the method including:

-   -   10) forming a first reaction mixture including        (R)-2-amino-2-phenylethan-1-ol or a salt thereof, a substrate, a        dehydrating agent or additive, and a first solvent to form        (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one:

-   -   11) forming a second reaction mixture including        (R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one, a Lewis        acid, a nucleophile, and a second solvent to form        (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one:

-   -   12) forming a third reaction mixture including        (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one, a reducing        agent, and a third solvent to form        (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol:

and

-   -   13) forming a fourth reaction mixture including        (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol, a        hydrogen source, a catalyst, an acid, and a fourth solvent to        provide the salt of (R)-2-amino-2-methylhexan-1-ol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can beprepared according to steps 10-13 as shown in the scheme of FIG. 4.

With respect to step 10, the substrate, the dehydrating agent oradditive, the first solvent, and reaction temperature are describedherein.

The substrate can be an alkyl pyruvate (e.g., methyl pyruvate or ethylpyruvate), pyruvic acid, or 2,2-diethoxypropionic acid ethyl ester. Insome embodiments, the substrate includes ethyl pyruvate. In someembodiments, the substrate can be ethyl pyruvate.

The dehydrating agent or additive can be an organic acid (e.g.,para-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid,trifluoromethanesulfonic acid, trifluoroacetic acid, or trichloroaceticacid), a metal halide (lithium chloride, magnesium chloride, or zincchloride), magnesium sulfate, sodium sulfate, an azeotropic removal ofwater (e.g., a Dean Stark trap), or 4 Å molecular sieves. In someembodiments, the dehydrating agent or additive includes 4 Å molecularsieves. In some embodiments, the dehydrating agent or additive can be 4Å molecular sieves.

The first solvent can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, ormethyl tert-butyl ether), an aromatic solvent (e.g., toluene,trifluorotoluene, benzene, or xylenes), a hydrocarbon solvent (e.g.,n-heptane, cyclohexane, or methylcyclohexane), an alcohol solvent (e.g,methanol, ethanol, 1-butanol, 2,2,2-trifluoroethanol, orhexafluoro-isopropanol), a chlorinated solvent (e.g., dichloromethane,1,2-dichlorethane, or chloroform), or combinations thereof. In someembodiments, the first solvent includes 2,2,2-trifluoroethanol. In someembodiments, the first solvent can be 2,2,2-trifluoroethanol.

In general, the cyclocondensation reaction (i.e., step 10) can beperformed at any suitable temperature, for example, at a temperature offrom 20° C. to 110° C. In some embodiments, the reaction mixture of thecyclocondensation reaction can be at a temperature of from 20° C. to areflux temperature. In some embodiments, the reaction mixture of thecyclocondensation reaction can be heated to reflux.

With respect to step 11, the Lewis acid, the nucleophile, the secondsolvent, and reaction temperature are described herein.

The Lewis acid can be boron trifluoride diethyl etherate, lithiumchloride, zinc chloride, titanium tetrachloride, silicon tetrachloride,aluminum chloride, samarium(II) iodide, cerium(III) chloride, orlanthanum(III) chloride lithium chloride complex. In some embodiments,the Lewis acid includes boron trifluoride diethyl etherate. In someembodiments, the Lewis acid can be boron trifluoride diethyl etherate.

The nucleophile can be n-butylmagnesium chloride, n-butyl lithium, orn-butylzinc bromide. In some embodiments, the nucleophile includesn-butylmagnesium chloride. In some embodiments, the nucleophile can ben-butylmagnesium chloride.

The second solvent can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyltert-butyl ether, or diethyl ether), an aromatic solvent (e.g., tolueneor trifluorotoluene), a hydrocarbon solvent (n-hexane, n-heptane,cyclohexane, or methylcyclohexane), a chlorinated solvent (e.g.,dichloromethane or chlorobenzene), or combinations thereof. In someembodiments, the second solvent includes tetrahydrofuran. In someembodiments, the second solvent can be tetrahydrofuran.

In general, the nucleophilic addition reaction (i.e., step 11) can beperformed at any suitable temperature, for example, at a temperature offrom −78° C. to −40° C.

With respect to step 12, the reducing agent, the third solvent, andreaction temperature are described herein.

The reducing agent can be lithium borohydride, lithium aluminum hydride,aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, boranecomplexes of tetrahydrofuran and dimethyl sulfide, lithiumtriethylborohydride, sodium borohydride aluminum chloride complex,lithium 9-boratabicyclo[3.3.1]nonane, diisobutylaluminum hydride,lithium tri-tert-butoxyaluminum hydride, or potassium borohydride. Insome embodiments, the reducing agent includes lithium borohydride. Insome embodiments, the reducing agent can be lithium borohydride.

The third solvent can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, methyltert-butyl ether, or diethyl ether), an aromatic solvent (e.g., toluene,xylene, or trifluorotoluene), a hydrocarbon solvent (e.g., n-hexane,n-heptane, or cyclohexane), or combinations thereof. In someembodiments, the third solvent includes tetrahydrofuran. In someembodiments, the third solvent can be tetrahydrofuran.

The reduction reaction mixture (i.e., step 12) can further include anadditive. The additive can be an alcohol (e.g., methanol, ethanol,n-butanol, isopropanol, or tert-butanol).

In general, the reduction reaction (i.e., step 12) can be performed atany suitable temperature, for example, at a temperature of from −40° C.to 50° C. In some embodiments, the reaction mixture of the reductionreaction can be at a temperature of from 0° C. to 20° C.

With respect to step 13, the hydrogen source, the catalyst, the acid,the fourth solvent, the salt of (R)-2-amino-2-methylhexan-1-ol, andreaction temperature are described herein.

The hydrogen source can be hydrogen gas, formic acid, ammonium formate,cyclohexene, hydrazine, or sodium hypophosphite. In some embodiments,the hydrogen source includes hydrogen gas. In some embodiments, thehydrogen source can be hydrogen gas.

The catalyst can be palladium hydroxide on carbon, palladium on carbon,or platinum oxide. In some embodiments, the catalyst includes palladiumhydroxide on carbon. In some embodiments, the catalyst can be palladiumhydroxide on carbon.

The acid can be a sulfonic acid (e.g., p-toluenesulfonic acid,methanesulfonic acid, or benzenesulfonic acid), a mineral acid (e.g.,hydrochloric acid or sulfuric acid), or an organic acid (e.g.,trifluoroacetic acid). In some embodiments, the acid includesp-toluenesulfonic acid. In some embodiments, the acid can bep-toluenesulfonic acid.

The fourth solvent can be an alcohol solvent (e.g., methanol, ethanol,or isopropanol), an organic acid solvent (e.g., acetic acid or formicacid), an ether (e.g., tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, cyclopentyl methyl ether, or tert-butyl methyl ether), apolar aprotic solvent (e.g., N-methyl-2-pyrrolidone,N,N-dimethylformamide, or N,N-dimethylacetamide), or combinationsthereof. In some embodiments, the fourth solvent includes ethanol. Insome embodiments, the fourth solvent can be ethanol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can be acompound of Formula VIb:

In general, the hydrogenation reaction (i.e., step 13) can be performedat any suitable temperature, for example, at a temperature of from 0° C.to 85° C. In some embodiments, the reaction mixture of the hydrogenationreaction can be at a temperature of from 20° C. to a reflux temperature.In some embodiments, the reaction mixture of the hydrogenation reactioncan be heated to reflux.

4. Preparation of a Salt of (R)-2-Amino-2-methylhexan-1-ol, Route 4

In some embodiments, the present disclosure provides a method forpreparing a salt of (R)-2-amino-2-methylhexan-1-ol:

the method including:

-   -   1) forming a first reaction mixture including an imine of C₁₋₄        alkyl alaninate having the formula:

-   -   an electrophile, a first base, a first catalyst, and a first        solvent to form an imine of C₁₋₄ alkyl        (R)-2-amino-2-methylhexanoate having the formula:

-   -   2a) forming a second reaction mixture including the imine of        C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate, a first acid and a        second solvent to form a crude first salt of        (R)-2-amino-2-methylhexanoate:

-   -   2b) triturating the crude first salt of        (R)-2-amino-2-methylhexanoate in the second solvent to provide        the first salt of (R)-2-amino-2-methylhexanoate;    -   3a) forming a third reaction mixture including the first salt of        (R)-2-amino-2-methylhexanoate, benzyl chloride, a second base, a        third solvent, and water to form a salt of        (R)-2-benzamido-2-methylhexanoic acid having the formula:

-   -   3b) forming a fourth reaction mixture including the salt of        (R)-2-benzamido-2-methylhexanoic acid, a second acid, a fourth        solvent, and water to form (R)-2-benzamido-2-methylhexanoic        acid;    -   4a) forming a fifth reaction mixture including        (R)-2-benzamido-2-methylhexanoic acid, a first reducing agent,        and a fifth solvent to form        (R)—N-(1-hydroxy-2-methylhexan-2-yl)benzamide having the        formula:

-   -   -   or a salt thereof;

    -   4b) forming a sixth reaction mixture including        (R)—N-(1-hydroxy-2-methylhexan-2-yl)benzamide or the salt        thereof, a second reducing agent, a second catalyst, a third        acid, and a sixth solvent to provide the salt of        (R)-2-amino-2-methylhexan-1-ol,        wherein R can be unsubstituted or substituted aryl or        unsubstituted or substituted aryl-CH═CH—.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can beprepared according to steps 1-4 as shown in the scheme of FIG. 14.

In some embodiments, C₁₋₄ alkyl in any one of formulae or compounds instep 1 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ortert-butyl. In some embodiments, C₁₋₄ alkyl in any one of formulae orcompounds in step 1 includes isopropyl. In some embodiments, C₁₋₄ alkylin any one of formulae or compounds in step 1 can be isopropyl. In someembodiments, C₁₋₄ alkyl in any one of formulae or compounds in step 1includes tert-butyl. In some embodiments, C₁₋₄ alkyl in any one offormulae or compounds in step 1 can be tert-butyl.

The imine of C₁₋₄ alkyl alaninate in Step 1 can be prepared according tothe methods as described herein, for example in Section 1 under SectionF, and in Example 8.

With respect to step 1, the imine of C₁₋₄ alkyl alaninate, theelectrophile, the first base, the first catalyst, the first solvent, theimine of C₁₋₄ alkyl (R)-2-amino-2-methylhexanoate, and reactiontemperature are described herein.

In some embodiments, the imine of C₁₋₄ alkyl alaninate has the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R includes 4-chlorophenyl. In some embodiments, the imine of C₁₋₄ alkylalaninate can be an imine of tert-butyl alaninate having the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be 4-chlorophenyl. In some embodiments, the imine of tert-butylalaninate can be tert-butyl 2-((4-chlorobenzylidene)amino)propanoate:

In some embodiments, the imine of tert-butyl alaninate can be a solutionof tert-butyl 2-((4-chlorobenzylidene)amino)propanoate in toluene.

In some embodiments, the electrophile can be n-butyl bromide, n-butyliodide, n-butyl methanesulphonate, n-butyl 4-methylbenzenesulfonate, orn-butyl sulfate. In some embodiments, the electrophile includes n-butylbromide. In some embodiments, the electrophile can be n-butyl bromide.

The first base can be a hydroxide (e.g., lithium hydroxide, sodiumhydroxide, potassium hydroxide, cesium hydroxide, rubidium hydroxide,barium hydroxide, calcium hydroxide, or tetra-n-butylammoniumhydroxide), an alkoxide (e.g., sodium methoxide, sodium tert-butoxide,potassium tert-butoxide, potassium isopropoxide, or sodiumtert-pentoxide), a carbonate (e.g., sodium carbonate, potassiumcarbonate, rubidium carbonate, magnesium carbonate, calcium carbonate,strontium carbonate, barium carbonate, or ammonium carbonate), a hydride(e.g., sodium hydride or potassium hydride), or combinations thereof. Insome embodiments, the first base includes potassium hydroxide andpotassium carbonate. In some embodiments, the first base can bepotassium hydroxide and potassium carbonate.

In some embodiments, the first catalyst can be a chiral auxiliary. Insome embodiments, the first catalyst can be N-benzylcinchonidiniumchloride, N-benzylcinchonidinium bromide,N-[4-(trifluoromethyl)benzyl]cinchoninium bromide,N-(9-anthracenylmethyl)cinchoninium chloride,(11bS)-(+)-4,4-Dibutyl-4,5-dihydro-2,6-bis(3,4,5-trifluorophenyl)-3H-dinaphth[2,1-c:1′,2′-e]azepiniumbromide,(11bS)-4,4-dibutyl-4,5-dihydro-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-3H-dinaphtho[2,1-c:1′,2′-e]phosphepiniumbromide, or O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide. Insome embodiments, the first catalyst includes N-benzylcinchoniumchloride (BCNC). In some embodiments, the first catalyst can beN-benzylcinchonium chloride (BCNC).

In some embodiments, the first solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether,methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinatesolvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene),an aromatic solvent (e.g., toluene, xylenes, anisole, ortrifluorotoluene), water, or combinations thereof. In some embodiments,the first solvent includes toluene. In some embodiments, the firstsolvent can be toluene.

In some embodiments, the imine of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate has the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be 4-chlorophenyl. In some embodiments, the imine of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate can be an imine of tert-butyl(R)-2-amino-2-methylhexanoate having the formula:

wherein R can be phenyl, 2-chlorophenyl, 4-chlorophenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-phenylvinyl,2-(4-methylphenyl)vinyl, 2-(4-hydroxy-3-methyoxyphenyl)vinyl,2-methylphenyl, 4-methylphenyl, or 4-methoxyphenyl. In some embodiments,R can be 4-chlorophenyl. In some embodiments, the imine of tert-butyl(R)-2-amino-2-methylhexanoate can be tert-butyl(R)-2-(chlorobenzylideneamino)-2-methylhexanoate:

In some embodiments, the imine of C₁₋₄ alkyl(R)-2-amino-2-methylhexanoate can be directly used in the following stepafter removal of the first solvent. In some embodiments, upon completionof the alkylation reaction, tert-butyl(R)-2-(chlorobenzylideneamino)-2-methylhexanoate can be directly used inthe following step after removal of the first solvent.

In some embodiments, the first reaction mixture upon completion can bedirectly used in the following step without removal of the firstsolvent. In some embodiments, upon completion of the alkylationreaction, the second reaction mixture including tert-butyl(R)-2-(chlorobenzylideneamino)-2-methylhexanoate and toluene can bedirectly used in the following step without removal of the solvent.

In general, the alkylation reaction (i.e., step 1) can be performed atany suitable temperature, for example, at a temperature of from −10° C.to 40° C. In some embodiments, the reaction mixture of the alkylationreaction can be at a temperature of from 0° C. to 30° C.

In some embodiments, step 2 includes two steps as described in steps 2aand 2b.

In some embodiments, with respect to steps 2a and 2b, the imine of C₁₋₄alkyl (R)-2-amino-2-methylhexanoate, the first acid, the second solvent,the first salt of (R)-2-amino-2-methylhexanoate, and reactiontemperature are described herein.

In some embodiments, the imine can be an imine of tert-butyl(R)-2-amino-2-methylhexanoate. In some embodiments, the imine can betert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate. In someembodiments, the imine can be the reaction mixture from step 1 includingtert-butyl (R)-2-(chlorobenzylideneamino)-2-methylhexanoate and toluene.

In some embodiments, the first acid can be a mineral acid (e.g.,hydrochloric acid, phosphoric acid, sulfuric acid, chlorosulfuric acid,or oleum), an organic acid (e.g., methanesulfonic acid, fumaric acid,acetic acid, formic acid, or ascorbic acid), or combinations thereof. Insome embodiments, the first acid includes hydrochloric acid. In someembodiments, the first acid can be hydrochloric acid. In someembodiments, the first acid can be in an aqueous solution. In someembodiments, the first acid includes an aqueous solution of hydrochloricacid. In some embodiments, the first acid can be an aqueous solution ofhydrochloric acid.

In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate canbe a hydrochloric acid salt thereof.

In some embodiments, the second solvent can be an aromatic solvent(toluene, xylenes, or trifluorotoluene), an ether (e.g., diethyl ether,methyl tert-butyl ether, tetrahydrofuran, or 1,4-dioxane), a chlorinatedsolvent (e.g., dichloromethane or 1,2-dichloroethane), an alcohol (e.g.,ethanol, 2-propanol, 1-butanol, tert-butanol, 2-methylbutan-2-ol, ortrifluoroethanol), a hydrocarbon solvent (e.g., n-heptane, hexanes,cyclohexane, or methylcyclohexane), or combinations thereof. In someembodiments, the second solvent includes 2-propanol. In someembodiments, the second solvent can be 2-propanol. In some embodiments,the second solvent includes toluene and 2-propanol. In some embodiments,the second solvent can be toluene and 2-propanol.

In some embodiments, the crude first salt of(R)-2-amino-2-methylhexanoate can be triturated with the second solventto provide the first salt of (R)-2-amino-2-methylhexanoate. In someembodiments, the crude first salt of (R)-2-amino-2-methylhexanoate canbe triturated with toluene to provide the first salt of(R)-2-amino-2-methylhexanoate. In some embodiments, the crudehydrochloric acid salt of (R)-2-amino-2-methylhexanoate can betriturated with toluene to provide the hydrochloric acid salt of(R)-2-amino-2-methylhexanoate. In some embodiments, the first salt of(R)-2-amino-2-methylhexanoate can be used directly in the following stepwithout purification. In some embodiments, the hydrochloric acid salt of(R)-2-amino-2-methylhexanoate can be used directly in the following stepwithout purification.

In general, the hydrolysis reaction (i.e., step 2a) can be performed atany suitable temperature, for example, at a temperature of from 20° C.to 80° C. In some embodiments, the reaction mixture of the hydrolysisreaction can be at a temperature of from 50° C. to 70° C. In general,the trituration (i.e., step 2b) can be performed at any suitabletemperature, for example, at a temperature of from 10° C. to 40° C. Insome embodiments, the trituration can be at room temperature.

In some embodiments, step 3 includes two steps as described in steps 3aand 3b.

In some embodiments, with respect to step 3a, the first salt of(R)-2-amino-2-methylhexanoate, the second base, the third solvent, thesalt of (R)-2-benzamido-2-methylhexanoic acid, and reaction temperatureare described herein.

In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate isthe hydrochloric acid salt thereof.

In some embodiments, the second base can be a hydroxide (e.g., lithiumhydroxide, sodium hydroxide, cesium hydroxide, or tetra-n-butylammoniumhydroxide), an alkoxide (e.g., sodium methoxide, sodium tert-butoxide,potassium tert-butoxide, or sodium tert-pentoxide), a carbonate (e.g.,sodium carbonate or potassium carbonate), a hydride (e.g., sodiumhydride or potassium hydride), an amine (e.g., triethylamine,tri-n-butylamine, N,N′-diisopropylethylamine, N-methylpyrrolidine,N-methylmorpholine, pyridine, 2,6-lutidine, collidine, or4-dimethylaminopyridine), or combinations thereof. In some embodiments,the second base can be in an aqueous solution. In some embodiments, thesecond base includes an aqueous solution of sodium hydroxide. In someembodiments, the second base can be an aqueous solution of sodiumhydroxide.

In some embodiments, the third solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether,methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinatesolvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene),an aromatic solvent (e.g., toluene, xylenes, anisole, ortrifluorotoluene), water, or combinations thereof. In some embodiments,the third solvent includes water. In some embodiments, the third solventcan be water.

In some embodiments, the salt of (R)-2-benzamido-2-methylhexanoic acidcan be a sodium salt thereof. In some embodiments, the sodium salt of(R)-2-benzamido-2-methylhexanoic acid can be used directly withoutpurification.

In general, the protection reaction (i.e., step 3a) can be performed atany suitable temperature, for example, at a temperature of from −10° C.to 50° C. In some embodiments, the reaction mixture of the protectionreaction can be at a temperature of from 0° C. to 30° C.

In some embodiments, with respect to step 3b, the salt of(R)-2-benzamido-2-methylhexanoic acid, the second acid, the fourthsolvent, and reaction temperature are described herein.

In some embodiments, the salt of (R)-2-benzamido-2-methylhexanoic acidis a sodium salt thereof.

In some embodiments, the second acid can be a mineral acid (hydrochloricacid, hydrobromic acid, phosphoric acid, or sulfuric acid), an organicacid (e.g., trichloroacetic acid or formic acid), or combinationsthereof. In some embodiments, the second acid can be in an aqueoussolution. In some embodiments, the second acid includes an aqueoussolution of hydrochloric acid. In some embodiments, the second acid canbe an aqueous solution of hydrochloric acid.

In some embodiments, the fourth solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether,methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinatesolvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene),an aromatic solvent (toluene, xylenes, anisole, or trifluorotoluene), analcohol (e.g., 2-propanol, 2-butanol, tert-butanol, 2-methylbutan-2-ol,2,2,2-trifluoroethanol, or hexafluoro-2-propanol), a ketone (methylisobutyl ketone, or methyl ethyl ketone), an ester (e.g., isopropylacetate, or n-butylacetate), water, or combinations thereof. In someembodiments, the fourth solvent includes water. In some embodiments, thefourth solvent can be water.

In general, the acidification reaction (i.e., step 3b) can be performedat any suitable temperature, for example, at a temperature of from −10°C. to 50° C. In some embodiments, the reaction mixture of theacidification reaction can be at a temperature of from 0° C. to 30° C.

In some embodiments, step 4 includes two steps as described in steps 4aand 4b.

In some embodiments, with respect to step 4a, the first reducing agent,the fifth solvent, and reaction temperature are described herein.

In some embodiments, the first reducing agent can be any suitablereducing agent capable of reducing an ester group (e.g., isopropylester) to the corresponding —CH₂OH. In some embodiments, the firstreducing agent can be diborane, borane tetrahydrofuran complex, boranedimethyl sulfide complex, borane dodecyl methyl sulfide complex, boranedimethylamine complex, borane ammonia complex, borane pyridine complex,borane trimethylamine complex, borane N,N-diethylaniline complex, boranemorpholine complex, borane methyl 6-morpholinohexyl sulfide complex,borane diphenylphosphine complex, sodium borohydride/boron trifluoride,lithium aluminum hydride, aluminum hydride, or diisobutylaluminumhydride. In some embodiments, the first reducing agent includes boranetetrahydrofuran complex. In some embodiments, the first reducing agentcan be borane tetrahydrofuran complex.

In some embodiments, the fifth solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, methyl tert-butyl ether, or diethyl ether), an aromaticsolvent (e.g., toluene, xylene, or trifluorotoluene), a hydrocarbonsolvent (e.g., n-hexane, n-heptane, or cyclohexane), or combinationsthereof. In some embodiments, the fifth solvent includestetrahydrofuran. In some embodiments, the fifth solvent can betetrahydrofuran.

In general, the reduction reaction (i.e., step 4a) can be performed atany suitable temperature, for example, at a temperature of from −40° C.to 80° C. In some embodiments, the reaction mixture of the reducingreaction can be at a temperature of from 25° C. to 65° C.

In some embodiments, with respect to step 4b, the second reducing agent,the second catalyst, the third acid, the sixth solvent, the salt of(R)-2-amino-2-methylhexan-1-ol, and reaction temperature are describedherein.

In some embodiments, the second reducing agent can be a hydrogen gas,formic acid, ammonium formate, cyclohexene, hydrazine, sodiumhypophosphite, or combinations thereof. In some embodiments, the secondreducing agent includes a hydrogen gas. In some embodiments, the secondreducing agent can be a hydrogen gas.

In some embodiments, the second catalyst can be a palladium catalyst. Insome embodiments, the second catalyst can be palladium hydroxide oncarbon, palladium on carbon, platinum on carbon, or platinum oxide. Insome embodiments, the second catalyst includes palladium hydroxide oncarbon. In some embodiments, the second catalyst can be palladiumhydroxide on carbon.

In some embodiments, the third acid can be a sulfonic acid (e.g.,para-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonicacid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), anorganic acid (e.g., trifluoroacetic acid). In some embodiments, thethird acid includes para-toluenesulfonic acid. In some embodiments, thethird acid can be para-toluenesulfonic acid.

In some embodiments, the sixth solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether,methyl tert-butyl ether, or cyclopentyl methyl ether), a chlorinatesolvent (e.g., dichloromethane, 1,2-dichloroethane, or chlorobenzene),an aromatic solvent (toluene, xylenes, anisole, or trifluorotoluene), analcohol (e.g., ethanol, 2-propanol, 2-butanol, tert-butanol,2-methylbutan-2-ol, 2,2,2-trifluoroethanol, or hexafluoro-2-propanol), aketone (e.g., methyl isobutyl ketone, or methyl ethyl ketone), an ester(e.g., isopropyl acetate or n-butylacetate), or combinations thereof. Insome embodiments, the sixth solvent includes ethanol. In someembodiments, the sixth solvent can be ethanol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can be acompound of Formula VIb:

In general, the Bz-deprotection reaction (i.e., step 4b) can beperformed at any suitable temperature, for example, at a temperature offrom 0° C. to 85° C. In some embodiments, the reaction mixture of theBz-deprotecting reaction can be at a temperature of from 20° C. to 80°C.

Alternatively, in some embodiments, the Bz-deprotection reaction of step4b can be achieved with lead tetraacetate or sodium periodate withbromine. 5. Preparation of a Salt of (R)-2-Amino-2-methylhexan-1-ol,Route 5,

In some embodiments, the present disclosure provides a method forpreparing a salt of (R)-2-amino-2-methylhexan-1-ol:

the method including:

-   -   1) forming a first reaction mixture including a first salt of        (R)-2-amino-2-methylhexanoate:

-   -   -   a reducing agent, and a first solvent to form            (R)-2-amino-2-methylhexan-1-ol having the formula:

-   -   2) forming a second reaction mixture including        (R)-2-amino-2-methylhexan-1-ol, an acid, and a second solvent to        provide the salt of (R)-2-amino-2-methylhexan-1-ol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can beprepared according to steps 1 and 2 as shown in the scheme of FIG. 15.

In some embodiments, the respect to step 1, the first salt of(R)-2-amino-2-methylhexanoate, the reducing agent, the first solvent,and reaction temperature are described herein.

In some embodiments, the first salt of (R)-2-amino-2-methylhexanoate isthe hydrochloric acid salt thereof.

In some embodiments, the reducing agent can be any suitable reducingagent capable of reducing an ester group (e.g., isopropyl ester) to thecorresponding —CH₂OH. In some embodiments, the reducing agent can bediborane, borane dimethyl sulfide complex, borane dodecyl methyl sulfidecomplex, borane dimethylamine complex, borane ammonia complex, boranepyridine complex, borane trimethyl amine complex, boraneN,N-diethylaniline complex, borane morpholine complex, borane methyl6-morpholinohexyl sulfide complex, sodium borohydride/boron trifluoride,diisobutylaluminum hydride, or lithium aluminum hydride. In someembodiments, the reducing agent includes lithium aluminum hydride. Insome embodiments, the reducing agent can be lithium aluminum hydride.

In some embodiments, the first solvent can be an ether (e.g.,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, methyl tert-butyl ether, or diethyl ether), an aromaticsolvent (e.g., toluene, xylene, or trifluorotoluene), a hydrocarbonsolvent (e.g., n-hexane, n-heptane, or cyclohexane), or combinationsthereof. In some embodiments, the first solvent includestetrahydrofuran. In some embodiments, the first solvent can betetrahydrofuran.

In general, the reduction reaction (i.e., step 1) can be performed atany suitable temperature, for example, at a temperature of from 0° C. to40° C. In some embodiments, the reaction mixture of the reductionreaction can be at a temperature of from 10° C. to 20° C.

In some embodiments, with respect to step 2, the acid, the secondsolvent, the salt of (R)-2-amino-2-methylhexan-1-ol, and reactiontemperature are described herein.

In some embodiments, the acid can be a sulfonic acid (e.g.,para-toluenesulfonic acid, methanesulfonic acid, or benzenesulfonicacid), a mineral acid (e.g., hydrochloric acid or sulfuric acid), anorganic acid (e.g., trifluoroacetic acid), or combinations thereof. Insome embodiments, the acid includes para-toluenesulfonic acid. In someembodiments, the acid can be para-toluenesulfonic acid.

In some embodiments, the second solvent can be an alcohol (methanol,ethanol, n-propanol, or n-butanol), an ether (e.g., diethyl ether,methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, or 1,2-dimethoxyethane), an aromatic solvent (e.g.,toluene, xylenes, fluorobenzene, or trifluorotoluene), a chlorinatedsolvent (e.g., dichloromethane or 1,2-dichloroethane), a ketone (e.g.,acetone or methyl isobutyl ketone), an ester (e.g., ethyl acetate, butylacetate, or isobutyl acetate), or combinations thereof. In someembodiments, the second solvent includes ethanol. In some embodiments,the second solvent can be ethanol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can be acompound of Formula VIb:

In general, the acidification reaction (i.e., step 2) can be performedat any suitable temperature, for example, at a temperature of from 0° C.to 100° C. In some embodiments, the reaction mixture of theacidification reaction can be at a temperature of from 15° C. to 30° C.

6. Preparation of a Salt of (R)-2-Amino-2-Methylhexan-1-Ol, Route 6

In some embodiments, the present disclosure provides a method forpreparing a salt of (R)-2-amino-2-methylhexan-1-ol:

the method including:

-   -   1) forming a first reaction mixture including        (2S,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one having the        formula:

-   -   -   or a salt thereof, an electrophile, a base, and a first            solvent to form            (2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one            having the formula:

-   -   -   or a salt thereof; and

    -   2) forming a second reaction mixture including        (2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one or        the salt thereof, an acid, and optional a second solvent to form        the salt of (R)-2-amino-2-methylhexan-1-ol.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can beprepared according to steps 1 and 2 as shown in the scheme of FIG. 16.

In some embodiments, with respect to step 1, the electrophile, the base,the first solvent, and reaction temperature are described herein.

In some embodiments, the electrophile can be n-butyl bromide, n-butyliodide, n-butyl methanesulphonate, n-butyl 4-methylbenzenesulfonate, orn-butyl sulfate. In some embodiments, the electrophile includes n-butyliodide. In some embodiments, the electrophile can be n-butyl iodide.

In some embodiments, the base can be lithium diisopropylamide, lithiumdiethylamide, lithium dicyclohexylamide, lithium dimethylamide, lithium2,2,6,6, -tetramethylpiperidide, lithium bis(trimethylsilyl)amide,sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide), orsodium hydride. In some embodiments, the base includes lithiumbis(trimethylsilyl)amide. In some embodiments, the base can be lithiumbis(trimethylsilyl)amide.

In some embodiments, the first solvent can be an aromatic solvent (e.g.,toluene, xylenes, chlorobenzene, fluorobenzene, or trifluorotoluene), anether (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran,2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g.,dichloromethane, or chlorobenzene), or combinations thereof. In someembodiments, the first solvent includes tetrahydrofuran. In someembodiments, the first solvent can be tetrahydrofuran.

In general, the alkylation reaction (i.e., step 1) can be performed atany suitable temperature, for example, at a temperature of from −100° C.to 0° C. In some embodiments, the reaction mixture of the alkylationreaction can be at a temperature of from −78° C. to −50° C.

In some embodiments, the alkylation reaction of step 1 can also includean additive. Suitable additives include, but are not limited to,hexamethylphosphoramide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, and1,3-dimethyl-2-imidazolidinone.

In some embodiments, with respect to step 2, the acid, the secondsolvent, the salt of (R)-2-amino-2-methylhexan-1-ol, and reactiontemperature are described herein.

In some embodiments, the acid can be a mineral acid (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid, or phosphoric acid), a sulfonicacid (e.g., para-toluenesulfonic acid, methanesulfonic acid, orbenzenesulfonic acid), an organic acid (e.g., trifluoroacetic acid). Insome embodiments, the acid includes hydrochloric acid. In someembodiments, the acid includes an aqueous solution of hydrochloric acid.In some embodiments, the acid can be hydrochloric acid. In someembodiments, the acid can be an aqueous solution of hydrochloric acid.

In some embodiments, the second solvent is absent. In some embodiments,the second solvent, when present, can be an alcohol (e.g., methanol,ethanol, or 2-propanol), an ether (e.g., diethyl ether, methyltert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane,or 1,2-dimethoxyethane), an aromatic solvent (toluene, xylenes,fluorobenzene, or trifluorotoluene), a chlorinated solvent (e.g.,dichloromethane or 1,2-dichloroethane), an ester (e.g., ethyl acetate,butyl acetate, or isobutyl acetate), water, or combinations thereof. Insome embodiments, the second solvent includes water. In someembodiments, the second solvent can be water.

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can be acompound of Formula VIb:

In some embodiments, the salt of (R)-2-amino-2-methylhexan-1-ol can be acompound of the Formula:

In general, the hydrolysis reaction (i.e., step 2) can be performed atany suitable temperature, for example, at a temperature of from 0° C. to120° C. In some embodiments, the reaction mixture of the hydrolysisreaction can be at a temperature of from 60° C. to 100° C.

7. Preparation of Compound of Formula VIIIb, Route 1

In some embodiments, the present disclosure provides a method forpreparing the compound of Formula VIIIb:

or a salt thereof, the method including:

-   -   14) forming a first reaction mixture including        2,3-dibromo-5-fluoropyridine or a salt thereof, a first        iodination reagent, an additive, and a first solvent to form        3-bromo-5-fluoro-2-iodopyridine:

-   -   -   or a salt thereof, or

    -   17) forming a second reaction mixture including        2,3-dibromo-5-fluoropyridine or a salt thereof, a second        iodination reagent, a catalyst, a first ligand, and a second        solvent to form 3-bromo-5-fluoro-2-iodopyridine or a salt        thereof,

    -   15) forming a third reaction mixture including        3-bromo-5-fluoro-2-iodopyridine or the salt thereof, a cyanation        reagent, a second ligand, and a third solvent to form        3-bromo-5-fluoropicolinonitrile:

-   -   -   or a salt thereof; and

    -   16) forming a fourth reaction mixture including        3-bromo-5-fluoropicolinonitrile or the salt thereof, an acid,        and a fourth solvent to provide the compound of Formula VIIIb or        the salt thereof, or        -   forming a fifth reaction mixture including            3-bromo-5-fluoropicolinonitrile or the salt thereof, an            enzyme, and a fifth solvent to provide the compound of            Formula VIIIb or the salt thereof.

In some embodiments, the compound of Formula VIIIb can be preparedaccording to steps 14-16 as shown in the scheme of FIG. 5A. In someembodiments, the compound of Formula VIIIb can be prepared according tosteps 17 as shown in the scheme of FIG. 5B and steps 15-16 as shown inthe scheme of FIG. 5A.

With respect to step 14, the first iodination reagent, the additive, thefirst solvent, and reaction temperature are described herein.

The first iodination reagent can be sodium iodide, lithium iodide,potassium iodide, cesium iodide, zinc iodide, magnesium iodide,copper(I) iodide, hydroiodic acid, trimethylsilyl iodide, or iodine. Insome embodiments, the first iodination reagent includes sodium iodide.In some embodiments, the first iodination reagent can be sodium iodide.

The additive can be water, trimethylsilyl chloride, an ammonium salt(e.g., tetra-n-butylammonium iodide), 2,6-di-tert-butylpyridine,2,6-di-tert-butyl-4-methylphenol, trimethylsilyltrifluoromethanesulfonate, an organic acid (e.g., acetic acid, formicacid, trichloroacetic acid, trifluoroacetic acid,trifluoromethanesulfonic acid, or methanesulfonic acid), a mineral acid(e.g., hydrochloric acid or sulfuric acid), a dehydrating agent (e.g.,bis(trimethylsilyl)acetamide, acetyl chloride, or triethylorthoformate), or combinations thereof. In some embodiments, theadditive includes trimethylsilyl chloride and water. In someembodiments, the additive can be trimethylsilyl chloride and water.

The first solvent can be an ester (e.g., ethyl acetate, butyl acetate,isopropyl acetate, or isobutyl acetate), an ether (e.g.,tetrahydrofuran, 2 methyltetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, or methyl tert-butyl ether), a polar aprotic solvent(e.g., acetonitrile, propionitrile, benzonitrile, N,N dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, orsulfolane), an aromatic solvent (e.g., toluene, trifluorotoluene,benzene, or xylenes), an organic acid solvent (e.g., acetic acid orformic acid), or combinations thereof. In some embodiments, the firstsolvent includes acetonitrile. In some embodiments, the first solventcan be acetonitrile.

In general, the halogen exchange reaction (i.e., step 14) can beperformed at any suitable temperature, for example, at a temperature offrom 20° C. to 110° C. In some embodiments, the reaction mixture of thehalogen exchange reaction can be at a temperature of from 20° C. to areflux temperature. In some embodiments, the reaction mixture of thehalogen exchange reaction can be heated to reflux.

In some embodiments, the halogen exchange reaction of step 14 can bereplaced with the halogen exchange reaction of step 17. With respect tostep 17, the second iodination reagent, the catalyst, the first ligand,the second solvent, and reaction temperature are described herein.

The second iodination reagent can be sodium iodide, lithium iodide,potassium iodide, cesium iodide, zinc iodide, or magnesium iodide. Insome embodiments, the second iodination reagent includes sodium iodide.In some embodiments, the second iodination reagent can be sodium iodide.

The catalyst can be copper(I) iodide, copper(II) iodide,copper(I)bromide, or copper(II)bromide. In some embodiments, thecatalyst includes copper(I) iodide. In some embodiments, the catalystcan be copper(I) iodide.

The first ligand can be trans-N,N′-dimethylcycloheane-1,2-diamine(DMCHDA), N,N,N′,N′-tetramethylethylenediamine, orN,N′-dimethylethylenediamine. In some embodiments, the first ligandincludes trans-N,N′-dimethylcycloheane-1,2-diamine. In some embodiments,the first ligand can be trans-N,N′-dimethylcycloheane-1,2-diamine.

The second solvent can be an ether (e.g., 1,4-dioxane or cyclopentylmethyl ether), an alcohol solvent (e.g., n-butanol, 1-hexanol,2-methylbutan-2-ol, or isopropanol), a polar aprotic solvent (e.g,benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, N-methyl-2-pyrrolidone, or sulfolane), an aromaticsolvent (e.g., toluene, trifluorotoluene, benzene, or xylenes), orcombinations thereof. In some embodiments, the second solvent includesn-butanol. In some embodiments, the second solvent can be n-butanol.

In general, the halogen exchange reaction (i.e., step 17) can beperformed at any suitable temperature, for example, at a temperature offrom 50° C. to 150° C. In some embodiments, the reaction mixture of thehydrolysis reaction can be at a temperature of from 80° C. to a refluxtemperature.

With respect to step 15, the cyanation reagent, the second ligand, thethird solvent, and reaction temperature are described herein.

The cyanation reagent can be copper (I) cyanide, sodium cyanide,potassium cyanide, or trimethylsilyl cyanide. In some embodiments, thecyanation reagent includes copper (I) cyanide. In some embodiments, thecyanation reagent can be copper (I) cyanide.

The second ligand can be absent or present. When the second ligand ispresent, the second ligand can be 1,10-phenanthroline,3,4,7,8-tetramethyl-1,10-phenanthroline,4,7-dichloro-1,10-phenanthroline, 4,7-dimethoxy-1,10-phenanthroline,trans-1,2-diaminocyclohexane, N,N′-dimethyl-1,2-cyclohexanediamine,4-dimethylaminopyridine, 8-hydroxyquinoline, tetramethylethylenediamine,L-proline, 1-butylimidazole, or 2-isobutylcyclohexanone. In someembodiments, the second ligand can be absent.

The third solvent can be an ester (e.g., butyl acetate, isopropylacetate, or isobutyl acetate,) an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, or cyclopentyl methyl ether), analcohol solvent (e.g., n-butanol, 2-methylbutan-2-ol, or isopropanol), apolar aprotic solvent (e.g., acetonitrile, propionitrile, benzonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,N-methyl-2-pyrrolidone, or sulfolane), an aromatic solvent (e.g.,toluene, benzene, xylenes, or trifluorotoluene), a chlorinated solvent(dichloromethane, 1,2-dichloroethane, chlorobenzene, or chloroform), orcombinations thereof. In some embodiments, the third solvent includesacetonitrile. In some embodiments, the third solvent can beacetonitrile.

In general, the cyanation reaction (i.e., step 15) can be performed atany suitable temperature, for example, at a temperature of from 20° C.to 120° C. In some embodiments, the reaction mixture of the cyanationreaction can be at a temperature of from 20° C. to a reflux temperature.In some embodiments, the reaction mixture of the cyanation reaction canbe heated to reflux.

With respect to step 16, the acid, the fourth solvent, the enzyme, andfifth solvent, and reaction temperature are described herein.

The acid can be sulfuric acid, phosphoric acid, hydrochloric acid,hydrobromic acid, chloric acid, perchloric acid, nitric acid,trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonicacid, or phthalic acid. In some embodiments, the acid includes sulfuricacid. In some embodiments, the acid can be sulfuric acid.

The fourth solvent can be water, an alcohol (e.g., methanol, ethanol,n-propanol, or isopropanol), or combinations thereof. In someembodiments, the fourth solvent includes water. In some embodiments, thefourth solvent can be water.

The hydrolysis reaction by the acid in step 16 can be replaced with anenzymatic hydrolysis reaction. In some embodiments, the enzymaticincludes a nitrilase enzyme. The enzymatic hydrolysis reaction can beperformed in an aqueous buffer solution with and without the addition ofan organic co-solvent. In some embodiments, the fifth solvent includesaqueous buffer solution. In some embodiments, the fifth solvent includesaqueous buffer solution and an organic co-solvent. The organicco-solvent can be an alcohol (e.g., methanol, ethanol, n-propanol, orisopropanol).

In some embodiments, the enzymatic can be a nitrilase enzyme. In someembodiments, the fifth solvent can be an aqueous buffer solution. Insome embodiments, the fifth solvent can be an aqueous buffer solutionand an organic co-solvent. The organic co-solvent can be an alcohol(e.g., methanol, ethanol, n-propanol, or isopropanol).

In general, the hydrolysis reaction (i.e., step 16) can be performed atany suitable temperature, for example, at a temperature of from 20° C.to 120° C. In some embodiments, the reaction mixture of the hydrolysisreaction can be at a temperature of from 20° C. to 100° C.

8. Preparation of Compound of Formula VIIIb, Route 2

In some embodiments, the present disclosure provides a method forpreparing the compound of Formula VIIIb:

or a salt thereof, the method including:

-   -   18a) forming a first reaction mixture including        5-fluoropicolinic acid or a salt thereof, an activating agent, a        promoter, and a first solvent to activate the —C(O)OH group of        5-fluoropicolinic acid, thereby forming an activated form of        5-fluoropicolinic acid or a salt thereof;    -   18b) forming a second reaction mixture including the activated        form of 5-fluoropicolinic acid or the salt thereof, an amine of        R⁶R⁷NH, a first base, and a second solvent to form a compound of        Formula XIII:

-   -   -   or a salt thereof;

    -   19) forming a third reaction mixture including the compound of        Formula XIII or the salt thereof, a brominating agent, a second        base, an additive, and a third solvent to form a compound of        Formula XIIb:

-   -   -   or a salt thereof; and

    -   20) forming a fourth reaction mixture including the compound of        Formula XIIb or the salt thereof, an acid, and a fourth solvent        to provide the compound of Formula VIIIb or the salt thereof,

-   wherein R⁶ and R⁷ are each independently hydrogen, C₁₋₄ alkyl, or    C₃₋₆ cycloalkyl, or R⁶ and R⁷ are combined to form a 3-6 membered    N-linked heterocycloalkyl, optionally having an additional 1-2    heteroatoms selected from O and S.

In some embodiments, the compound of Formula VIIIb or the salt thereofcan be prepared according to steps 18-20 as shown in the scheme of FIG.6.

Step 18 includes steps 18a and 18b.

With respect to step 18a, the activating agent, the promoter, the firstsolvent, the activated form of 5-fluoropicolinic acid, and reactiontemperature are described herein. With respect to step 18b, the amine ofR⁶R⁷NH, the first base, the second solvent, the compound of FormulaXIII, and reaction temperature are described herein.

The activating agent can be a chlorinating agent. In some embodiments,the chlorinating agent can be oxalyl chloride, thionyl chloride,phosphorus(V) oxychloride, phosphorus(V) pentachloride, or(chloromethylene)dimethyliminium chloride. In some embodiments, theactivating (or chlorinating) agent includes oxalyl chloride. In someembodiments, the activated form of 5-fluoropicolinic acid can be5-fluoropicolinoyl chloride.

The activating agent can be any peptide coupling reagent capable ofactivating an acid group (e.g., the acid group of 5-fluoropicolinicacid), thereby reacting with an amine (e.g., the amine in step 18b) toform an amide bond (e.g., the amide group of Formula XIII). In someembodiments, the activating agent can be 1,1′-carbonyldiimidazole orisobutyl chloroformate. In some embodiments, the activated form of5-fluoropicolinic acid can be(5-fluoropyridin-2-yl)(1H-imidazol-1-yl)methanone or 5-fluoropicolinic(isobutyl carbonic) anhydride.

The promoter can be N,N-dimethylformamide, N,N-dimethylacetamide, ordichloromethylene-dimethyliminium chloride. In some embodiments, thepromoter includes N,N-dimethylformamide. In some embodiments, thepromoter can be N,N-dimethylformamide.

The amine of R⁶R⁷NH can be a primary amine (e.g., ethyl amine,isopropylamine, tert-butylamine, or cyclohexylamine) or a secondaryamine (e.g., diethyl amine or morpholine). In some embodiments, theamine of R⁶R⁷NH can be tert-butylamine.

The first base can be absent or present. When the base is present, thebase can be a tertiary amine (e.g., triethylamine,N,N-diisopropylethylamine, N-methylpyrrolidine, or N-methylmorpholine),an aromatic amine base (e.g., pyridine), or an inorganic base (e.g.,sodium hydroxide, sodium carbonate, sodium bicarbonate, potassiumhydroxide, potassium carbonate, cesium carbonate, or potassium phosphatetribasic). In some embodiments, the first base can be absent.

The first and second solvents can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, methyl tert-butyl ether, or 1,4-dioxane), achlorinated solvent (e.g., dichloromethane, chloroform, or1,2-dichloroethane, etc.), an aromatic solvent (e.g., benzene, toluene,or xylenes), or combinations thereof. In some embodiments, the firstsolvent includes 2-methyltetrahydrofuran. In some embodiments, thesecond solvent includes 2-methyltetrahydrofuran. The second reactionmixture (i.e., step 18b) can further include water to have a biphasicreaction. In some embodiments, the first solvent can be2-methyltetrahydrofuran. In some embodiments, the second solvent can be2-methyltetrahydrofuran. The second reaction mixture (i.e., step 18b)can further include water to have a biphasic reaction.

With respect to the amine of R⁶R⁷NH or the compound of Formula XIII, R⁶and R⁷ are as defined and described herein.

In some embodiments, R⁶ can be hydrogen or C₁₋₄ alkyl. The C₁₋₄ alkylcan be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ortert-butyl. In some embodiments, R⁶ can be hydrogen or ethyl. In someembodiments, R⁶ can be hydrogen. In some embodiments, R⁶ can be ethyl.

In some embodiments, R⁷ can be C₁₋₄ alkyl or C₃₋₆ cycloalkyl. The C₁₋₄alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ortert-butyl. The C₃₋₆ cycloalkyl can be cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In some embodiments, R⁷ can be ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or cyclohexyl. Insome embodiments, R⁷ can be ethyl, isopropyl, tert-butyl, or cyclohexyl.In some embodiments, R⁷ can be tert-butyl.

In some embodiments, R⁶ can be hydrogen; and R⁷ can be C₁₋₄ alkyl, orC₃₋₆ cycloalkyl. In some embodiments, R⁶ can be hydrogen; and R⁷ can beethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, orcyclohexyl. In some embodiments, R⁶ can be hydrogen; and R⁷ can beethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R⁶ canbe hydrogen and R⁷ can be tert-butyl. In some embodiments, R⁶ can beethyl; and R⁷ can be C₁₋₄ alkyl. In some embodiments, R⁶ and R⁷ can eachbe ethyl.

In some embodiments, R⁶ and R⁷ can be combined to form N-linkedmorpholinyl.

In some embodiments, the compound of Formula XIII can beN-(tert-butyl)-5-fluoropicolinamide having the formula:

or a salt thereof.

In some embodiments, N-(tert-butyl)-5-fluoropicolinamide can be isolatedas a solution in methylcyclohexane and used directly in the followingstep without purification and/or removal of methylcyclohexane. In someembodiments, N-(tert-butyl)-5-fluoropicolinamide can be isolated as asolution in 1,4-dioxane and used directly in the following step withoutpurification and/or removal of 1,4-dioxane. In some embodiments,N-(tert-butyl)-5-fluoropicolinamide can be isolated as a solution inmethyl cyclopentyl ether and used directly in the following step withoutpurification and/or removal of methyl cyclopentyl ether.

In general, the reactions of step 18a and step 18b can be performed atany suitable temperature, for example, at a temperature of from 5° C. to60° C. In some embodiments, the reaction mixtures of both step 18a andstep 18b can be at a temperature of from 15° C. to 30° C.

Step 19 includes steps 19a and 19b. Step 19a includes a metalation stepand step 19b includes a bromination step.

With respect to step 19, the brominating agent, the second base, theadditive, the third solvent, the compound of Formula XIIb, and reactiontemperature are described herein.

In some embodiments, the compound of Formula XIII can beN-(tert-butyl)-5-fluoropicolinamide or a salt thereof. In someembodiments, N-(tert-butyl)-5-fluoropicolinamide or the salt thereof canbe the solution thereof in methylcyclohexane. In some embodiments,N-(tert-butyl)-5-fluoropicolinamide or the salt thereof can be thesolution thereof in 1,4-dioxane. In some embodiments,N-(tert-butyl)-5-fluoropicolinamide or the salt thereof can be thesolution thereof in methylcyclopentyl ether.

The brominating agent can be bromine, N-bromosuccinimide,triphenylphosphine dibromide, tetrabutylammonium tribromide,trimethylphenylammonium tribromide, N-bromoacetamide, pyridiniumtribromide, dibromodimethylhydantoin, tribromoisocyanuric acid,N-bromosaccharin, or 1,2-dibromo-1,1,2,2-tetrachloroethane. In someembodiments, the brominating agent includes bromine. In someembodiments, the brominating agent can be bromine.

The second base can be a metal amide base (e.g., lithiumdiisopropylamide, 2,2,6,6-tetramethylpiperidinylmagnesium chloride,lithium 2,2,6,6-tetramethylpiperidide,bis(2,2,6,6-tetramethylpiperidinyl)magnesium, ordi-n-butyllithium(2,2,6,6-tetramethylpiperidinyl)magnesate), an alkyl-and alkenylmetal (n-butyllithium, isopropylmagnesium chloride,tri-n-butyllithium magnesate, di-n-butylmagnesium, ethyln-butylmagnesium, or di-sec-butylmagnesium). In some embodiments, thebase includes di-n-butylmagnesium. In some embodiments, the base can bedi-n-butylmagnesium.

The additive can be absent or present. When the additive is present, theadditive can be lithium chloride, lanthanum (III) chloride,N,N′-dimethylpropyleneurea, N,N,N′,N′-tetramethylethylenediamine, orhexamethylphosphoramide. In some embodiments, the additive can beabsent.

The third solvent can be an ether (tetrahydrofuran,2-methyltetrahydrofuran, methyl tert-butyl ether, methyl cyclopentylether, or 1,4-dioxane), a nonpolar solvent (e.g., cyclohexane,methylcyclohexane, or n-heptane), an aromatic solvent (e.g., benzene,toluene, or xylenes), a chlorinated solvent (e.g, dichloromethane,1,2-dichloroethane, or chlorobenzene), or combinations thereof. In someembodiments, the third solvent includes methylcyclohexane. In someembodiments, the third solvent can be methylcyclohexane.

With respect to the compound of Formula XIIb, R⁶ and R⁷ are defined anddescribed herein (also see Section IV, compounds of Formula XII). Insome embodiments, R⁶ can be hydrogen; and R⁷ can be ethyl, isopropyl,tert-butyl, or cyclohexyl. In some embodiments, R⁶ can be hydrogen andR⁷ can be tert-butyl. In some embodiments, R⁶ can be ethyl; and R⁷ canbe C₁₋₄ alkyl. In some embodiments, R⁶ and R⁷ can each be ethyl. In someembodiments, R⁶ and R⁷ can be combined to form N-linked morpholinyl.

In some embodiments, the compound of Formula XIIb can be of FormulaXIIc:

or a salt thereof.

In general, the metalation step (i.e., step 19a) in the brominationreaction (i.e., step 19) can be performed at any suitable temperature,for example, at a temperature of from room temperature to a refluxtemperature. In some embodiments, the reaction mixture of the metalationstep in the bromination reaction can be at a temperature of from 30° C.to 80° C. In general, the bromination step (i.e., step 19b) in thebromination reaction (i.e., step 19) can be performed at any suitabletemperature, for example, at a temperature of from −40° C. to 0° C. Insome embodiments, the reaction mixture of the bromination step in thebromination reaction can be at a temperature of from −40° C. to −15° C.

With respect to step 20, the acid, the fourth solvent, and reactiontemperature are described herein.

The acid can be sulfuric acid, phosphoric acid, hydrochloric acid,hydrobromic acid, chloric acid, perchloric acid, nitric acid,trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonicacid, or phthalic acid. In some embodiments, the acid includes sulfuricacid. In some embodiments, the acid can be sulfuric acid.

The fourth solvent can be water. In some embodiments, the solventincludes water.

In general, the hydrolysis reaction (i.e., step 20) can be performed atany suitable temperature, for example, at a temperature of from 20° C.to 100° C. In some embodiments, the reaction mixture of the hydrolysisreaction can be at a temperature of from 50° C. to 100° C.

9. Preparation of Compound of Formula XIb, Route 1

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula XIb:

or a salt thereof, the method including:

-   -   21) forming a first reaction mixture including        2-bromo-5-fluoropyridin-3-amine or a salt thereof, a cyanide        source, a catalyst, and a first solvent to form        3-amino-5-fluoropicolinonitrile:

-   -   -   or a salt thereof;

    -   22) forming a second reaction mixture including        3-amino-5-fluoropicolinonitrile or the salt thereof, carbon        dioxide, a first base, and a second solvent to form        7-fluoropyrido[3,2-d]pyrimidine-2,4-diol:

-   -   -   or a salt thereof; and

    -   23) forming a third reaction mixture including        7-fluoropyrido[3,2-d]pyrimidine-2,4-diol, a chlorinating agent,        a second base, and a third solvent to form the compound of        Formula XIb or the salt thereof.

In some embodiments, the compound of Formula XIb can be preparedaccording to steps 21-23, as shown in the scheme of FIG. 7A.

With respect to step 21, the cyanide source, the catalyst, the firstsolvent, and reaction temperature are described herein.

The cyanide source can be zinc cyanide, potassium ferricyanide,copper(I) cyanide, potassium cyanide, sodium cyanide, trimethylsilylcyanide, acetone cyanohydrin, hexamethylenetetramine, or ethylcyanoacetate. In some embodiments, the cyanide source includes zinccyanide. In some embodiments, the cyanide source can be zinc cyanide.

The catalyst can be a palladium catalyst with or without a tertiaryphosphine ligand (e.g., tetrakis(triphenylphosphine)palladium (0),tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate,palladium(II) chloride, bis(triphenylphosphine)palladium(II) dichloride;bis(acetonitrile)palladium(II) dichloride,(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride,palladium(π-cinnamyl) chloride dimer, or(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate), a copper(I) catalyst with or without a diamine oramino acid ligand (e.g., copper(I) cyanide, copper(I) iodide, copper(I)bromide, or copper(I) chloride), or a nickel(II) catalyst (e.g.,(N,N,N′N′-tetramethylethylenediamine)NiCl(o-tolyl) ortrans-chloro-(2-napthyl)-bis(triphenylphosphine)nickel(II)). In someembodiments, the catalyst includes tetrakis(triphenylphosphine)palladium(0). In some embodiments, the catalyst can betetrakis(triphenylphosphine)palladium (0).

The first solvent can be a polar aprotic solvent (e.g.,N,N-dimethylformamide, N-methyl-2-pyrrolidone, orN,N-dimethylacetamide), an ether (e.g., 1,4-dioxane, tetrahydrofuran,2-methyltetrahydrofuran, or 1,2-dimethoxyethane), an alcohol (e.g,methanol, ethanol, 1-butanol, or 2 propanol), an aromatic solvent (e.g.,toluene, xylenes, or anisole), or combinations thereof. The firstsolvent can further include water. In some embodiments, the firstsolvent includes N,N-dimethylformamide. In some embodiments, the firstsolvent can be N,N-dimethylformamide.

In general, the cyanation reaction (i.e., step 21) can be performed atany suitable temperature, for example, at a temperature of from 40° C.to 140° C. In some embodiments, the reaction mixture of the cyanationreaction can be at a temperature of from 80° C. to 110° C.

With respect to step 22, the first base, the second solvent, andreaction temperature are described herein.

The first base can be 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), tetramethylguanidine,1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), ortert-butylimino-tri(pyrrolidino)phosphorene. In some embodiments, thefirst base includes 1,8-diazabicyclo[5.4.0]undec-7-ene. In someembodiments, the first base can be 1,8-diazabicyclo[5.4.0]undec-7-ene.

The second solvent can be a polar aprotic solvent (e.g,N,N-dimethylformamide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide,dimethylsulfoxide, or sulfolane), an aromatic amine base (e.g.,pyridine, 2,6-lutidine, or collidines), an ether (e.g., 1,4-dioxane orcyclopentyl methyl ether), a chlorinated solvent (e.g.,1,2-dichloroethane or chlorobenzene), an aromatic solvent (e.g.,toluene, xylenes, or trifluorotoluene, etc.), or combinations thereof.In some embodiments, the second solvent includes N,N-dimethylformamide.In some embodiments, the second solvent can be N,N-dimethylformamide.

In general, the cyclization reaction (i.e., step 22) can be performed atany suitable temperature, for example, at a temperature of from 40° C.to 150° C. In some embodiments, the reaction mixture of the cyclizationreaction can be at a temperature of from 40° C. to 60° C.

With respect to step 23, the chlorinating agent, the second base, thethird solvent, and reaction temperature are described herein.

The chlorinating agent can be phosphorus oxychloride, phosphorus(V)chloride, or triphenylphosphine dichloride. In some embodiments, thechlorinating agent includes phosphorus oxychloride. In some embodiments,the chlorinating agent can be phosphorus oxychloride.

The second base can be present or absent. When the second base ispresent, the second base can be a tertiary amine (e.g., triethylamine,tri-n-butylamine, N,N-diisopropylethylamine, dimethylaniline, ordiethylaniline), or an aromatic amine base (e.g., pyridine,2,6-lutidine, or collidines). In some embodiments, the second baseincludes N,N-diisopropylethylamine. In some embodiments, the second basecan be N,N-diisopropylethylamine.

The third solvent can be absent and the chlorination reaction can beperformed in neat phosphorus oxychloride. When the third solvent ispresent, the third solvent can be an aromatic solvent (e.g., toluene orxylenes), an aromatic amine solvent (e.g., diethylaniline), achlorinated solvent (e.g, chlorobenzene), or combinations thereof. Insome embodiments, the third solvent includes toluene. In someembodiments, the third solvent can be toluene.

In general, the chlorination reaction (i.e., step 23) can be performedat any suitable temperature, for example, at a temperature of from 50°C. to 140° C. In some embodiments, the reaction mixture of thechlorination reaction can be at a temperature of from 80° C. to 120° C.

10. Preparation of Compound of Formula XIb, Route 2

In some embodiments, the above step 22 can be replaced with steps 24 and25, as shown in the scheme of FIG. 7B.

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula XIb:

or a salt thereof, the method including:

-   -   21) forming a first reaction mixture including        2-bromo-5-fluoropyridin-3-amine or a salt thereof, a cyanide        source, a catalyst, and a first solvent to form        3-amino-5-fluoropicolinonitrile:

-   -   -   or a salt thereof;

    -   24) forming a second reaction mixture including including        3-amino-5-fluoropicolinonitrile or the salt thereof, an oxidant,        a first base, and a second solvent to form        3-amino-5-fluoropicolinamide:

-   -   -   or a salt thereof;

    -   25) forming a third reaction mixture including        3-amino-5-fluoropicolinamide or the salt thereof, a cyclization        reagent, and a third solvent to form        7-fluoropyrido[3,2-d]pyrimidine-2,4-diol:

-   -   -   or a salt thereof; and

    -   23) forming a fourth reaction mixture including        7-fluoropyrido[3,2-d]pyrimidine-2,4-diol or the salt thereof, a        chlorinating agent, a second base, and a fourth solvent to form        the compound of Formula XIb or the salt thereof.

Steps 21 and 23 are described above in the preparation of the compoundof Formula XIb, Route 1.

With respect to step 24, the oxidant, the first base, the secondsolvent, and reaction temperature are described herein.

The oxidant can be hydrogen peroxide, hydrogen peroxide urea adduct,lithium peroxide, benzoyl peroxide, or tert-butyl peroxide. In someembodiments, the oxidant includes hydrogen peroxide. In someembodiments, the oxidant can be in an aqueous solution. In someembodiments, the oxidant can be an aqueous solution of hydrogenperoxide. In some embodiments, the oxidant can be hydrogen peroxide.

The first base can be an alkali carbonate (e.g., sodium carbonate,potassium carbonate, or cesium carbonate); or an alkali hydroxide (e.g.,sodium hydroxide, potassium hydroxide, or ammonium hydroxide). In someembodiments, the first base includes potassium carbonate. In someembodiments, the first base can be potassium carbonate.

The second solvent can be a polar aprotic solvent (e.g.,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, or dimethylsulfoxide), analcohol (e.g., methanol, ethanol, or tert-butanol), 1,4-dioxane, water,or combinations thereof. In some embodiments, the second solventincludes dimethylsulfoxide. In some embodiments, the second solvent canbe dimethylsulfoxide.

In general, the oxidation reaction (i.e., step 24) can be performed atany suitable temperature, for example, at a temperature of from 20° C.to 120° C. In some embodiments, the reaction mixture of the oxidationreaction can be at a temperature of from 20° C. to 40° C.

The oxidation reaction of step 24 can be replaced with a hydrolysisreaction using a mineral acid. In some embodiments,3-amino-5-fluoropicolinonitrile or the salt thereof can be subjected tohydrolysis by a mineral acid, for example, sulfuric acid, to form3-amino-5-fluoropicolinamide or the salt thereof.

With respect to step 25, the cyclization reagent, the third solvent, andreaction temperature are described herein.

The cyclization reagent can be triphosgene, 1,1′-carbonyldiimidazole,phosgene, diphosgene, diphenylcarbonate, or sodium cyanate. In someembodiments, the cyclization reagent includes triphosgene. In someembodiments, the cyclization reagent can be triphosgene.

The third solvent can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, or 1,4-dioxane); an aromatic solvent (e.g.,toluene or xylenes), a polar aprotic solvent (e.g., acetonitrile,propionitrile, or n-butylnitrile), an organic acid (e.g., acetic acid orchloroacetic acid), or combinations of thereof. In some embodiments, thethird solvent includes 1,4-dioxane. In some embodiments, the thirdsolvent can be 1,4-dioxane.

In general, the cyclization reaction of step 25 can be performed at anysuitable temperature, for example, at a temperature of from 20° C. to150° C. In some embodiments, the reaction mixture of the cyclizationreaction can be at a temperature of from 90° C. to 110° C.

11. Preparation of Formula IXa

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula IXa:

the method including forming a guanylation reaction mixture including aguanylation reagent, (2,4-dimethoxyphenyl)methanamine, a base, anadditive, and a solvent to form the compound of Formula IXb, wherein ncan be from 0 to 1.

The guanylation reagent can be thiourea, 1H-pyrazole-1-carboxamidinehydrochloride, cyanamide,N,N-di-tert-butyloxycarbonyl-1H-pyrazole-1-carboxamidine,N,N-di-tert-butyloxycarbonyl-thiourea, S—C₁₋₆ alkyl isothiourea (e.g.,S-methylisothiourea, S-ethylisothiourea, S-butylisothiourea,S-tert-butyl-isothiourea, or S-hexylisothiourea), or a salt thereof. Insome embodiments, the guanylation reagent includes S—C₁₋₆ alkylisothiourea. In some embodiments, the guanylation reagent includesS-methylisothiourea. In some embodiments, the guanylation reagentincludes S-methylisothiourea hemisulfate. In some embodiments, theguanylation reagent can be S—C₁₋₆ alkyl isothiourea. In someembodiments, the guanylation reagent can be S-methylisothiourea. In someembodiments, the guanylation reagent can be S-methylisothioureahemisulfate.

The base can be absent or present. When the base is present, the basecan be a tertiary amine (e.g., triethylamine, tri-n-butylamine, orN,N-diisopropylethylamine). In some embodiments, the base can be absent.

The additive can be absent or present. When the additive is present, theadditive can be a Lewis acid (e.g., tris-dimethylamino-aluminum dimer orscandium triflate). In some embodiments, the additive can be absent.

The solvent can be an ether (e.g., tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, or cyclopentyl methyl ether,etc.), an alcohol (e.g., methanol, ethanol, n-butanol,2-methylbutan-2-ol, or isopropanol), water, a polar aprotic solvent(N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, or sulfolane), a chlorinated solvent (e.g.,dichloromethane, 1,2-dichloroethane, chlorobenzene, or chloroform) orcombinations thereof. In some embodiments, the solvent includesN-methyl-2-pyrrolidone. In some embodiments, the solvent can beN-methyl-2-pyrrolidone.

In some embodiments, the compound of Formula IXa can be of Formula IXb:

In some embodiments, the present disclosure provides a method forpreparing a compound of Formula IXb:

the method including forming a guanylation reaction mixture includingS-methylisothiourea hemisulfate, (2,4-dimethoxyphenyl)methanamine, andN-methyl-2-pyrrolidone to form the compound of Formula IXb.

In general, the guanylation reaction can be performed at any suitabletemperature, for example, at a temperature of from 20° C. to 130° C. Insome embodiments, the reaction mixture of the guanylation reaction canbe at a temperature of from 50° C. to 110° C.

12. Preparation of C₁₋₄ alkyl 2-amino-2-methylhexanoate via2-amino-2-methylhexanenitrile

In some embodiments, the present disclosure provides a method forpreparing C₁₋₄ alkyl 2-amino-2-methylhexanoate:

or a salt thereof, the method including:

-   -   1) forming a first reaction mixture including hexan-2-one having        the formula:

-   -   -   a cyanide, optionally a first acid, a desiccant, optionally            an additive, and a first solvent to form            2-amino-2-methylhexanenitrile having the formula:

-   -   -   or a salt thereof;

    -   2a) forming a second reaction mixture including        2-amino-2-methylhexanenitrile or the salt thereof, a C₁₋₄ alkyl        alcohol, a second acid, and water to form a salt of C₁₋₄ alkyl        2-amino-2-methylhexanoate; and

    -   2b) forming a third reaction mixture including the salt of C₁₋₄        alkyl 2-amino-2-methylhexanoate, a base, and a second solvent to        form C₁₋₄ alkyl 2-amino-2-methylhexanoate in a neutral form.

In some embodiments, C₁₋₄ alkyl 2-amino-2-methylhexanoate can beisopropyl 2-amino-2-methylhexanoate having the formula:

In some embodiments, isopropyl 2-amino-2-methylhexanoate can be preparedaccording to steps as shown in the scheme of FIG. 13.

In some embodiments, the C₁₋₄ alkyl in C₁₋₄ alkyl2-amino-2-methylhexanoate or the salt thereof can be methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In someembodiments, the C₁₋₄ alkyl in C₁₋₄ alkyl 2-amino-2-methylhexanoate orthe salt thereof can be isopropyl.

In some embodiments, with respect to step 1, the cyanide, the firstacid, the desiccant, the additive, the first solvent, and reactiontemperature are described herein.

In some embodiments, the cyanide can be hydrogen cyanide, sodiumcyanide, potassium cyanide, ammonium cyanide, trimethylsilyl cyanide,tert-butyldimethylsilyl cyanide, potassium hexacyanoferrate(III),potassium hexacyanoferrate(II), sodium ferrocyanide, acetonecyanohydrin, triphenyl acetonitrile, ethyl cyanoformate, diethylcyanophosphate, acetyl cyanide, or combinations thereof. In someembodiments, the cyanide includes sodium cyanide. In some embodiments,the cyanide can be sodium cyanide.

In some embodiments, the first acid is absent. In some embodiments, thefirst reaction mixture further comprises a first acid. The first acidcan be ammonium chloride, para-toluenesulfonic acid, oxalic acid, formicacid, acetic acid, guanidine hydrochloric acid, cyanuric acid,hydrochloric acid, sulfuric acid, phosphoric acid, or combinationsthereof. In some embodiments, the acid includes ammonium chloride. Insome embodiments, the acid can be ammonium chloride.

In some embodiments, the desiccant can be magnesium sulfate, sodiumsulfate, a trialkyl orthoformate (e.g., trimethyl orthoformate), anazeotropic removal of water (e.g., a Dean Stark trap), or molecularsieves. In some embodiments, the desiccant includes magnesium sulfate.

In some embodiments, the additive is absent. In some embodiments, thefirst reaction mixture further comprises an additive. In someembodiments, the additive can be a Lewis acid includingscandium(III)triflate, boron trifluoride etherate, zinc iodide, lithiumchlorite, trimethylsilyl trifluoromethanesulfonate, bismuth chloride,magnesium bromide, ruthenium(III) chloride, or combinations thereof.

In some embodiments, the first solvent can be an alcohol (e.g.,methanol, ethanol, 2-propanol, 1-butanol, tert-butanol,2-methylbutan-2-ol, or trifluoroethanol), a hydrocarbon solvent (e.g.,n-heptane, hexanes, cyclohexane, or methylcyclohexane), a polar aproticsolvent (e.g., acetonitrile, propionitrile, or butyronitrile), anorganic acid (e.g., acetic acid, formic acid, or trifluoroacetic acid),a chlorinated solvent (e.g., dichloromethane or chlorobenzene), anaromatic solvent (e.g., toluene, xylene, nitrobenzene, trifluorotoluene,or fluorobenzene), water, or combinations thereof. In some embodiments,the first solvent includes methanol. In some embodiments, the firstsolvent can be methanol.

In general, the first reaction (i.e., step 1) can be performed at anysuitable temperature. For example, the first reaction mixture can be ata temperature of from 0° C. to 70° C. In some embodiments, the firstreaction mixture can be at a temperature of from 0° C. to 40° C.

In some embodiments, step 2 includes two steps as described in steps 2aand 2b.

In some embodiments, with respect to step 2a, the C₁₋₄ alkyl alcohol,the second acid, the salt of C₁₋₄ alkyl 2-amino-2-methylhexanoate, andreaction temperature are described herein.

In some embodiments, the C₁₋₄ alkyl alcohol can be methanol, ethanol,n-propanol, isopropanol, n-butanol, sec-butanol, or tert-butanol. Insome embodiments, the C₁₋₄ alkyl alcohol includes methanol. In someembodiments, the C₁₋₄ alkyl alcohol can be methanol.

In some embodiments, the second acid can be a mineral acid (e.g.,sulfuric acid, hydrochloric acid, phosphoric acid, chlorosulfuric acid,oleum, fluorosulfuric acid, or fluoroantimonic acid), an organic acid(e.g., methanesulfonic acid or triflic acid), or combinations thereof.In some embodiments, the second acid includes sulfuric acid. In someembodiments, the second acid can be sulfuric acid

In some embodiments, the salt of C₁₋₄ alkyl 2-amino-2-methylhexanoatecan be a sulfuric acid salt, hydrochloric acid salt, phosphoric acidsalt, chlorosulfuric acid salt, oleum salt, fluorosulfuric acid salt,fluoroantimonic acid salt, methanesulfonic acid salt, or triflic acidsalt. In some embodiments, the salt of C₁₋₄ alkyl2-amino-2-methylhexanoate can be a sulfate. In some embodiments, thesalt of C₁₋₄ alkyl 2-amino-2-methylhexanoate can be isopropyl2-amino-2-methylhexanoate sulfate.

In general, the second reaction (i.e., step 2a) can be performed at anysuitable temperature. For example, the second reaction mixture can be ata temperature of from 50° C. to 150° C. In some embodiments, the secondreaction mixture can be at a temperature of from 70° C. to 100° C.

In some embodiments, with respect to step 2b, the base, the secondsolvent, and reaction temperature are described herein.

In some embodiments, the base can be an inorganic base (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumphosphate tribasic, or potassium phosphate tribasic), an organic base(e.g., sodium acetate, potassium acetate, sodium methoxide, sodiumtert-butoxide, or potassium tert-butoxide), or combinations thereof. Insome embodiments, the base includes sodium hydroxide. In someembodiments, the base can be sodium hydroxide. In some embodiments, thebase can be in an aqueous solution. In some embodiments, the baseincludes an aqueous solution of sodium hydroxide. In some embodiments,the base can be an aqueous solution of sodium hydroxide.

In some embodiments, the second solvent can be an aromatic solvent(e.g., toluene, xylenes, or trifluorotoluene), an ether (e.g., diethylether, methyl tert-butyl ether, tetrahydrofuran,2-methyltetrahydrofuran, or 1,4-dioxane), a chlorinated solvent (e.g.,dichloromethane, or 1,2-dichloroethane), or combinations thereof. Insome embodiments, the second solvent includes 2-methyltetrahydrofuran.In some embodiments, the second solvent can be 2-methyltetrahydrofuran.

In general, the third reaction (i.e., step 2b) can be performed at anysuitable temperature. For example, the third reaction mixture can be ata temperature of from 0° C. to 40° C. In some embodiments, the thirdreaction mixture can be at a temperature of from 20° C. to 30° C.

IV. Compounds

In another embodiment, the present disclosure provides a compound ofFormula III:

or a salt thereof, wherein R¹, R², and R³ can each independently behydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogenor methyl; R⁵ can be C₃₋₆ alkyl; and X can be F, Cl, Br, I, or OTs.

In another embodiment, the present disclosure provides a compound ofFormula III:

or a salt thereof, wherein R¹, R², and R³ can each independently behydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogenor methyl; R⁵ can be C₃₋₆ alkyl; and X can be Cl, Br, I, or OTs.

In some embodiments, R² can be Cl, F, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃alkoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy. The C₁₋₃ alkyl can be methyl, ethyl,propyl, or isopropyl. The C₁₋₃ alkoxy can be methoxy, ethoxy, n-propoxy,or iso-propoxy. In some embodiments, R² can be Cl, F, CN, CF₃, methyl,ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy;and R¹ and R³ can each independently be hydrogen, F, Cl, CN, CF₃,methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃, methyl,ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy;and R¹ and R³ can each be hydrogen. In some embodiments, R² can be F,and R¹ and R³ can each be hydrogen.

In some embodiments, R⁴ can be hydrogen. In some embodiments, R⁴ can bemethyl.

In some embodiments, R⁵ can be C₃₋₆ alkyl. In some embodiments, R⁵ canbe n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, or hexyl. In some embodiments, R⁵ can be n-butyl.

In some embodiments, R⁴ can be methyl; and R⁵ can be C₃₋₆ alkyl. In someembodiments, R⁴ can be methyl; and R⁵ can be n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl.In some embodiments, R⁴ can be methyl; and R⁵ can be n-butyl.

In some embodiments, X can be F, Br, I, or OTs. In some embodiments, Xcan be Br, I, or OTs. In some embodiments, X can be Br. In someembodiments, X can be F.

In some embodiments, the compound of Formula III can be of Formula IIIa:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula III can be of FormulaIIIa-1:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula III can be of Formula IIIb:

or a salt thereof.

In some embodiments, the compound of Formula III can be of FormulaIIIb-1:

or a salt thereof.

In another embodiment, the present disclosure provides a compound ofFormula IV:

or a salt thereof, wherein R¹, R², and R³ can each independently behydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogenor methyl; R⁵ can be C₃₋₆ alkyl; X can be F, Cl, Br, I, or OTs; and AG¹can be Cl, Br, OSO₃H, OSO₃, OMs, OTs, or OTf.

In another embodiment, the present disclosure provides a compound ofFormula IV:

or a salt thereof, wherein R¹, R², and R³ can each independently behydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogenor methyl; R⁵ can be C₃₋₆ alkyl; X can be Cl, Br, I, or OTs; and AG¹ canbe Cl, Br, OMs, OTs, or OTf.

In some embodiments, R² can be Cl, F, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃alkoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy. The C₁₋₃ alkyl can be methyl, ethyl,n-propyl, or isopropyl. The C₁₋₃ alkoxy can be methoxy, ethoxy,n-propoxy, or isopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃,methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃, methyl,ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy;and R¹ and R³ can each be hydrogen. In some embodiments, R² can be F,and R¹ and R³ can each be hydrogen.

In some embodiments, R⁴ can be hydrogen. In some embodiments, R⁴ can bemethyl.

In some embodiments, R⁵ can be C₃₋₆ alkyl. In some embodiments, R⁵ canbe n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, or hexyl. In some embodiments, R⁵ can be n-butyl.

In some embodiments, R⁴ can be methyl; and R⁵ can be C₃₋₆ alkyl. In someembodiments, R⁴ can be methyl; and R⁵ can be n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl.In some embodiments, R⁴ can be methyl; and R⁵ can be n-butyl.

In some embodiments, X can be F, Br, I, or OTs. In some embodiments, Xcan be Br, I, or OTs. In some embodiments, X can be Br. In someembodiments, X can be F.

In some embodiments, AG¹ can be Cl. In some embodiments, AG¹ can be Br.In some embodiments, AG¹ can be OMs, OTs, or OTf. In some embodiments,AG¹ can be OSO₃H or OSO₃ ⁻

In some embodiments, the compound of Formula IV can be of Formula IV-1:

or a salt thereof, wherein R¹, R², R³, R⁴, R⁵, and X are defined anddescribed herein.

In some embodiments, the compound of formula IV-1 can be of FormulaIVa-1:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of formula IV-1 can be of FormulaIVa-2:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula IV-1 can be of FormulaIVb-1:

or a salt thereof.

In some embodiments, the compound of Formula IV-1 can be of FormulaIVb-2:

or a salt thereof.

In another embodiment, the present disclosure provides a compound ofFormula V:

or a salt thereof, wherein R¹, R², and R³ can each independently behydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogenor methyl; R⁵ can be C₃₋₆ alkyl; and X can be F, Cl, Br, I, or OTs.

In another embodiment, the present disclosure provides a compound ofFormula V:

or a salt thereof, wherein R¹, R², and R³ can each independently behydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ can be hydrogenor methyl; R⁵ can be C₃₋₆ alkyl; and X can be Cl, Br, I, or OTs.

In some embodiments, R² can be Cl, F, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃alkoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy. The C₁₋₃ alkyl can be methyl, ethyl,n-propyl, or isopropyl. The C₁₋₃ alkoxy can be methoxy, ethoxy,n-propoxy, or isopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃,methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃, methyl,ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or iso-propoxy;and R¹ and R³ can each be hydrogen. In some embodiments, R² can be F,and R¹ and R³ can each be hydrogen.

In some embodiments, R⁴ can be hydrogen. In some embodiments, R⁴ can bemethyl.

In some embodiments, R⁵ can be C₃₋₆ alkyl. In some embodiments, R⁵ canbe n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, or hexyl. In some embodiments, R⁵ can be n-butyl.

In some embodiments, R⁴ can be methyl; and R⁵ can be C₃₋₆ alkyl. In someembodiments, R⁴ can be methyl; and R⁵ can be n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or hexyl.In some embodiments, R⁴ can be methyl; and R⁵ can be n-butyl.

In some embodiments, X can be F, Br, I, or OTs. In some embodiments, Xcan be Br, I, or OTs. In some embodiments, X can be Br. In someembodiments, X can be F.

In some embodiments, the compound of Formula V is not

-   3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,-   3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide,-   3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,-   3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,-   3,6-dichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,-   3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,-   3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,-   3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or-   3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.

In some embodiments, the compound of Formula V can be of Formula Va:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula V can be of Formula Va-1:

or a salt thereof, wherein R² and R⁵ are defined and described herein.

In some embodiments, the compound of Formula V can be of Formula Vb:

or a salt thereof.

In some embodiments, the compound of Formula V can be of Formula Vb-1:

or a salt thereof.

In another embodiment, the present disclosure provides a compound ofFormula XII:

or a salt thereof, wherein

-   -   R¹, R², and R³ are each independently hydrogen, F, Cl, CN, CF₃,        C₁₋₃ alkyl, or C₁₋₃ alkoxy; and    -   R⁶ and R⁷ are each independently hydrogen, C₁₋₄ alkyl, or C₃₋₆        cycloalkyl, or    -   R⁶ and R⁷ are combined to form a 3-6 membered N-linked        heterocycloalkyl, optionally having an additional 1-2        heteroatoms selected from O and S,    -   provided that at least one of R¹, R², and R³ can be F, Cl, CN,        CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy.

In some embodiments, R² can be Cl, F, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃alkoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy. The C₁₋₃ alkyl can be methyl, ethyl,n-propyl, or isopropyl. The C₁₋₃ alkoxy can be methoxy, ethoxy,n-propoxy, or isopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃,methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy; and R¹ and R³ can each independently be hydrogen, F, Cl, CN,CF₃, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, orisopropoxy. In some embodiments, R² can be Cl, F, CN, CF₃, methyl,ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy;and R¹ and R³ can each be hydrogen. In some embodiments, R¹ and R³ caneach be hydrogen and R² can be F.

In some embodiments, R⁶ can be hydrogen or C₁₋₄ alkyl. The C₁₋₄ alkylcan be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ortert-butyl. In some embodiments, R⁶ can be hydrogen or ethyl. In someembodiments, R⁶ can be hydrogen. In some embodiments, R⁶ can be ethyl.

In some embodiments, R⁷ can be C₁₋₄ alkyl or C₃₋₆ cycloalkyl. The C₁₋₄alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ortert-butyl. The C₃₋₆ cycloalkyl can be cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In some embodiments, R⁷ can be ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or cyclohexyl. Insome embodiments, R⁷ can be ethyl, isopropyl, tert-butyl, or cyclohexyl.In some embodiments, R⁷ can be tert-butyl.

In some embodiments, R⁶ can be hydrogen; and R⁷ can be C₁₋₄ alkyl, orC₃₋₆ cycloalkyl. In some embodiments, R⁶ can be hydrogen; and R⁷ can beethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, orcyclohexyl. In some embodiments, R⁶ can be hydrogen; and R⁷ can beethyl, isopropyl, tert-butyl, or cyclohexyl. In some embodiments, R⁶ canbe hydrogen and R⁷ can be tert-butyl. In some embodiments, R⁶ can beethyl; and R⁷ can be C₁₋₄ alkyl. In some embodiments, R⁶ and R⁷ can eachbe ethyl.

In some embodiments, R⁶ and R⁷ can be combined to form N-linkedmorpholinyl.

In some embodiments, R¹ and R³ can each be hydrogen; R² can be F; R⁶ canbe hydrogen; and R⁷ can be tert-butyl.

In some embodiments, the compound of Formula XII can be of Formula XIIa:

or a salt thereof, wherein R², R⁶, and R⁷ are defined and describedherein.

In some embodiments, the compound of Formula XII can be of Formula XIIb:

or a salt thereof, wherein R⁶ and R⁷ are defined and described herein.

In some embodiments, the compound of Formula XII can be of Formula XIIc:

or a salt thereof.

In some embodiments, the compound of Formula XII is not3-bromo-N-(tert-butyl)picolinamide or3,5-dibromo-N-(tert-butyl)picolinamide.

In some embodiments, the compound of Formula XVIII can be of theFormula:

or a salt thereof.

In some embodiments, the compound of Formula XVIII can be of theFormula:

or a salt thereof.

V. Examples Example 1: Preparation of(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide(Compound of Formula Vb)

Oxalyl chloride (1.1 equiv) was charged over about 15 minutes to areaction vessel containing 3-bromo-5-fluoropicolinic acid (scalingfactor, 1.00 equiv) and N,N-dimethylformamide (0.1 equiv) in2-methyltetrahydrofuran (10 volumes). The mixture was aged at about 20°C. The acid chloride mixture was transferred to a second reactorcontaining (R)-2-amino-2-methylhexan-1-ol 4-methylbenzenesulfonate salt(1.0 equiv) and potassium carbonate (3.0 equiv) in water (10 volumes)over approximately 30 minutes. The reaction mixture was aged at about20° C. Agitation was stopped and the phases were allowed to separate.The aqueous layer was discharged, and the organics were washed withwater (5 volumes). The final organic layer was azeotropically dried, andthe volume was adjusted to about 10 volumes by the addition of2-methyltetrahydrofuran. The compound of Formula Vb was then isolated.¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (d, J=2.5 Hz, 1H), 8.27 (dd, J=8.5,2.5 Hz, 1H), 7.86 (br s, 1H), 4.82 (t, J=5.6 Hz, 1H), 3.53 (dd, J=10.7,5.7 Hz, 1H), 3.46 (dd, J=10.7, 5.6 Hz, 1H), 1.77 (m, 1H), 1.67 (m, 1H),1.32-1.22 (m, 4H), 1.27 (s, 3H), 0.88 (m, 3H).

Example 2: Preparation of(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole(Compound of Formula IIIb)

Thionyl chloride (1.2 equiv) was charged over approximately 15 min to areaction vessel containing the solution of the compound of Formula Vb(1.0 equiv, prepared from Example 1) in 2-methyltetrahydrofuran (10volumes). The mixture was aged at about 50° C. The contents wereadjusted to about 10° C., and the reaction mixture was washed with 10 wt% aqueous sodium hydroxide and water. To the organic solution of thecompound of formula IVb-1 was charged n-Bu₄HSO₄ (0.1 equiv.), followedby a 10 wt % sodium hydroxide solution in water (3.5 volumes). Thecontents were adjusted to about 35° C., and aged at this temperature.The contents were adjusted to about 20° C., and agitation was stoppedand the layers were allowed to separate. The aqueous layer wasdischarged, and the organic layer was washed with water. Followingazeotropic drying, the compound of Formula IIIb was isolated. ¹H NMR(500 MHz, CDCl₃): δ 8.50 (d, J=2.0 Hz, 1H), 7.76 (dd, J=7.5, 2.5 Hz,1H), 4.27 (d, J=8.0 Hz, 1H), 4.12 (d, J=8.5 Hz, 1H), 1.69-1.43 (m, 3H),1.42 (s, 3H), 1.36-1.34 (m, 3H), 0.92 (t, J=7.0 Hz, 3H).

Example 3: Preparation of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Compound of Formula IIb)

A reaction vessel was charged with DMB-NHC(═NH)NH₂.½ H₂SO₄ (1.2 equiv),copper(II) acetate (0.15 equiv), potassium phosphate tribasic (4 equiv),and acetonitrile (6.6 volumes) and was agitated at about 20° C. Asolution of the compound of Formula IIIb (1.0 equiv, scaling factor) in2-methyltetrahydrofuran (3.3 volumes) was charged to the reactor. Thereaction mixture was heated to reflux for approximately 4 hours. Thecontents were cooled to about 20° C., charged with2-methyltetrahydrofuran (5 volumes) and an aqueous solution of 5 wt %ethylenediaminetetraacetic acid disodium salt dihydrate (10 volumes),and the mixture was agitated for approximately 30 minutes. The phaseswere allowed to separate and the aqueous phase was partitioned. Theorganics were further washed with aqueous 5 wt %ethylenediaminetetraacetic acid disodium salt dihydrate, 10 wt %potassium carbonate, and water. The solvent was exchanged toacetonitrile and the contents were heated to reflux. The mixture wascooled to about 45° C. over approximately 3 hours, then cooled to about0° C. over approximately 5 hours and held at about 0° C. forapproximately 7 hours. The resulting slurry was filtered, and the cakewas washed with acetonitrile (2.5 volumes) and dried to provide thecompound of Formula IIb. ¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, J=2.5 Hz,1H), 7.32-7.29 (m, 2H), 7.10 (br s, 1H), 6.47 (d, J=2.53 Hz, 1H), 6.43(dd, J=8.2, 2.4 Hz, 1H), 4.55 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H),3.79-3.72 (m, 2H), 2.01-1.91 (m, 1H), 1.75 (dt, J=13.3, 6.8 Hz, 1H),1.47-1.29 (m, 7H), 0.92 (t, J=7.0 Hz, 3H).

Example 4: Preparation of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Compound of Formula Ib)

A reaction vessel was charged with the compound of Formula IIb (1.0equiv, scaling factor) and dichloromethane (2 volumes) and the contentswere agitated. Trifluoroacetic acid (7.8 equiv) was charged to thevessel at a rate to maintain the internal temperature at about 30° C.The reaction mixture was heated to about 30° C. and aged forapproximately 8 hours. The contents were cooled to 20° C. Ethanol (3.2volumes) was charged and the contents were aged for approximately 14hours. The slurry was filtered and the residue was washed with ethanol.The filtrate was charged to a reaction vessel and concentrated toapproximately 3 volumes. The contents were cooled to about 20° C. andethanol (1.3 volumes) and water (1.0 volume) were charged to thereaction vessel. The pH was adjusted to about 12 with the addition of asolution of aqueous 50 wt % sodium hydroxide. The contents were cooledto about 20° C. and water (3 volumes) was charged over about 30 minutes.The contents are further cooled to about 0° C. over approximately 2hours and aged at this temperature for about 2 hours. The slurry wasfiltered and the wet-cake was washed with a mixture of ethanol and waterand dried to provide the compound of Formula Ib. ¹H NMR (500 MHz,Methanol-d₄) δ 8.23 (d, J=2.5 Hz, 1H), 7.25 (dd, J=10.0, 2.5 Hz, 1H),3.92 (d, J=11.5 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H), 2.08-1.81 (m, 2H),1.46 (s, 3H), 1.35-1.29 (m, 4H), 0.91 (t, J=7.0 Hz, 3H).

Example 5: Preparation of(R)-2-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Compound of Formula IXb)

A reaction vessel was charged with the compound of Formula Xb (scalingfactor, 1.0 equiv), the compound of Formula VIb (1.0 equiv),2-methyltetrahydrofuran (3 volumes), isopropyl acetate (7 volumes), andN,N-diisopropylethylamine (2.2 equiv). The reaction mixture was agitatedand heated to about 80° C. for approximately 6 hours. The reactionmixture was cooled to about 40° C., then washed with 10 wt % aqueouspotassium carbonate (12 volumes) and water (10 volumes). The compound ofFormula IXb was isolated. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=2.6 Hz,1H), 7.97 (dd, J=9.6 Hz, 2.6 Hz, 1H), 7.79 (s, 1H), 5.06 (br s, 1H),3.72 (d, J=10.9 Hz, 1H), 3.50 (d, J=10.9 Hz, 1H), 1.97-1.84 (m, 2H),1.42 (s, 3H), 1.31-1.16 (m, 4H), 0.89-0.78 (m, 3H).

Example 6: Preparation of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Compound of Formula IIb)

A reaction vessel was charged with the compound of Formula IXb (1.0equiv, prepared from Example 5) as a solution in 2-methyltetrahydrofuranand isopropyl acetate. Potassium carbonate (1.4 equiv) and2,4-dimethoxybenzylamine (2.0 equiv) were charged to the reactionvessel. The reaction mixture was heated to about 70° C. forapproximately 16 hours. The reaction mixture was cooled to about 35° C.and washed with water (10 volumes), 5 wt % aqueous acetic acid (10volumes), 10 wt % aqueous potassium carbonate (10 volumes), and water(10 volumes). The organic layer was concentrated to about 7 volumes,crude compound of Formula IIb (0.5 wt %) was charged, and the mixturewas agitated for approximately 1 hour. n-Heptane (17 volumes) wascharged over approximately 2 hours, then the slurry was cooled to about20° C. over approximately 1 hour and agitated for approximately 1 hour.The slurry was filtered, and the cake was washed with a mixture ofn-heptane (2.1 volumes) and isopropyl acetate (0.85 volumes), and driedto provide the compound of Formula IIb. ¹H NMR (500 MHz, DMSO-d₆) δ 8.08(s, 1H), 7.30-7.26 (m, 2H), 7.05 (s, 1H), 6.44 (s, 1H), 6.41 (d, J=8.0Hz, 1H), 4.54 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 (m, 2H),1.95-1.72 (m, 2H), 1.41-1.27 (m, 7H), 0.90 (t, J=7.0 Hz, 3H).

Example 7: Preparation of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(Compound of Formula Ib)

A reaction vessel was charged with the compound of Formula IIb (1.0equiv, scaling factor) and dichloromethane (13 volumes) and the contentswere agitated. Trifluoroacetic acid (9.7 equiv) was charged to thevessel at a rate to maintain the internal temperature at about 40° C.The reaction mixture was heated to about 40° C. and aged forapproximately 3 hours. The contents were cooled to 25° C. Ethanol (4.0volumes) was charged and the contents were aged for approximately 24hours. The slurry was filtered and the cake was washed withdichloromethane. The filtrate was charged to a reaction vessel and water(6.8 volumes), ethyl acetate (13.5 volumes) and 30 wt % aqueous sodiumhydroxide (3.2 volumes) were charged and the contents were heated toabout 40° C. with agitation. The aqueous layer was partitioned and theorganic layer was washed with 4.5 wt % aqueous sodium bicarbonate (5.0volumes) and water (5.0 volumes). Following azeotropic drying from ethylacetate, the contents were heated to about 80° C. and aged forapproximately 30 minutes. The contents were cooled to about 20° C. overapproximately 1 hour. The slurry was filtered and the wet-cake waswashed with ethyl acetate (5 volumes) to provide the compound of FormulaIb. ¹H NMR (500 MHz, Methanol-d₄) δ 8.23 (d, J=2.5 Hz, 1H), 7.25 (dd,J=10.0, 2.5 Hz, 1H), 3.92 (d, J=11.5 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H),2.08-1.81 (m, 2H), 1.46 (s, 3H), 1.35-1.29 (m, 4H), 0.91 (t, J=7.0 Hz,3H).

Example 8: Preparation of (R)-2-Amino-2-methylhexan-1-olp-Toluenesulfonic Acid Salt (Compound of Formula VIb) According to FIG.3A Step-1: Preparation of Isopropyl (E)-2-(benzylideneamino)propanoate

A reaction vessel was charged with the HCl salt of isopropyl L-alaninate(1.0 equiv, scaling factor) and toluene (5 volumes) and the contentswere agitated at about 20° C. Triethylamine (1.5 equiv), sodium sulfate(0.6 equiv) and benzaldehyde (1.01 equiv) were charged to the reactionvessel. The slurry was agitated at about 20° C. for approximately 20hours. The slurry was filtered and the cake was washed with toluene (2volumes). Isopropyl (E)-2-(benzylideneamino)propanoate was thenisolated. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.81-7.73 (m, 2H),7.53-7.39 (m, 3H), 4.93 (hept, J=6.2 Hz, 1H), 4.14 (q, J=6.7 Hz, 1H),1.38 (d, J=6.7 Hz, 3H), 1.17 (dd, J=12.3, 6.2 Hz, 6H).

Step 2: Preparation of Isopropyl 2-amino-2-methylhexanoate

A reaction vessel was charged with isopropyl(E)-2-(benzylideneamino)propanoate (1.0 equiv, prepared from Example 8)in toluene (7 volumes). 1-Bromobutane (1.2 equiv) was charged to thereaction vessel, and the contents were heated to about 40° C. Sodiumisopropoxide (1.2 equiv, 20% wt/wt in tetrahydrofuran) was charged tothe reaction vessel, and the reaction mixture was agitated forapproximately 4 hours. The reaction mixture was cooled to about 15° C.and 10 wt % aqueous sulfuric acid (1.2 equiv) was charged to thereaction vessel. The mixture was agitated at about 20° C. forapproximately 1 hour. The phases were allowed to separate, and theaqueous layer was partitioned. The organic layer was washed with water(2 volumes). The combined aqueous layers were charged to a separatereaction vessel and extracted with 2-methyltetrahydrofuran (5 volumes)and aqueous 50 wt % sodium hydroxide (2.5 equiv). Isopropyl2-amino-2-methylhexanoate was isolated. ¹H NMR (400 MHz, DMSO-d₆) δ 4.86(hept, J=6.3 Hz, 1H), 1.68 (br s, 2H), 1.59-1.48 (m, 1H), 1.47-1.35 (m,1H), 1.24-1.19 (m, 4H), 1.16 (d, J=6.3 Hz, 6H), 1.14 (s, 3H), 0.83 (t,J=7.1 Hz, 3H).

Step-3: Preparation of Isopropyl 2-amino-2-methylhexanoate PhosphateSalt

To a reaction vessel containing isopropyl 2-amino-2-methylhexanoate (1.0equiv, scaling factor) in 2-methyltetrahydrofuran (8 volumes) wascharged a mixture of aqueous 85 wt % phosphoric acid (1.05 equiv) and2-methyltetrahydrofuran (2 volumes). The resulting slurry was agitatedat about 20° C. for approximately 15 hours. The slurry was filtered andthen the cake was washed with 2-methyltetrahydrofuran and dried. ¹H NMR(400 MHz, DMSO-d₆) δ 7.02 (br s, 5H), 4.88 (hept, J=6.2 Hz, 1H),1.65-1.57 (m, 2H), 1.28 (s, 3H), 1.34-1.08 (m, 3H), 1.16 (d, J=6.3 Hz,6H), 1.08-0.95 (m, 1H), 0.80 (t, J=7.2 Hz, 3H).

Step-4: Preparation of Isopropyl (R)-2-amino-2-methylhexanoate

A reaction vessel was charged with the phosphate salt of isopropyl2-amino-2-methylhexanoate (1.0 equiv, scaling factor), a solution ofpotassium phosphate tribasic (1.37 equiv) in water (24 volumes), andacetone (6 volumes). The mixture was agitated and heated to about 30° C.Alcalase© (2 volumes) was charged to the reaction vessel and the mixturewas agitated at about 30° C. for approximately 20 hours. The reactionmixture was cooled to about 20° C., charged with methyl tert-butyl ether(20 volumes) and aqueous 45 wt % potassium hydroxide (2.0 equiv), andagitated for approximately 30 minutes. The phases were allowed toseparate, and the aqueous layer was partitioned. Isopropyl(R)-2-amino-2-methylhexanoate was isolated. ¹H NMR (400 MHz, DMSO-d₆) δ4.86 (hept, J=6.3 Hz, 1H), 1.68 (br s, 2H), 1.59-1.48 (m, 1H), 1.47-1.35(m, 1H), 1.24-1.19 (m, 4H), 1.16 (d, J=6.3 Hz, 6H), 1.14 (s, 3H), 0.83(t, J=7.1 Hz, 3H).

Step-5: Preparation of Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate

A reaction vessel was charged with isopropyl(R)-2-amino-2-methylhexanoate equiv, scaling factor) as a solution inmethyl tert-butyl ether (10 volumes). Di-tert-butyl dicarbonate (1.2equiv) was charged to the reaction vessel and the mixture was agitatedat about 20° C. for approximately 24 hours. Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate was isolated. ¹HNMR (400 MHz, DMSO-d₆) δ 7.00 (br s, 1H), 4.86 (hept, J=6.3 Hz, 1H),1.69 (ddd, J=16.1, 11.7, 4.9 Hz, 1H), 1.57 (ddd, J=13.3, 10.8, 5.3 Hz,1H), 1.36 (s, 9H), 1.26 (s, 3H), 1.30-1.06 (m, 4H), 1.14 (d, J=6.3 Hz,6H), 0.84 (t, J=7.1 Hz, 3H).

Step-6: Preparation of tert-Butyl(R)-(1-hydroxy-2-methylhexan-2-yl)carbamate

A reaction vessel was charged with a solution of isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate (1.0 equiv, scalingfactor) in methyl tert-butyl ether (10 volumes). Lithium borohydridesolution (2.2 equiv, 5% wt/wt in tetrahydrofuran) was slowly charged tothe vessel, and the reaction mixture was agitated at about 20° C.Methanol (2.2 equiv) as a solution in methyl tert-butyl ether (1.5volumes) was charged to the reaction vessel. The reaction mixture wasagitated for approximately 1 hour at about 20° C. A separate vessel wascharged with citric acid monohydrate (2.5 equiv) and water (10 volumes).The contents of the reaction vessel were transferred to the vesselcontaining citric acid in water, and then the mixture was agitated forapproximately 15 minutes. The phases were allowed to separate, and theaqueous layer was partitioned. The organic layer was washed with waterand tert-butyl (R)-(1-hydroxy-2-methylhexan-2-yl)carbamate was isolated.¹H NMR (400 MHz, DMSO-d₆) δ 6.02 (br s, 1H), 4.62 (t, J=5.8 Hz, 1H),3.35 (dd, J=10.6, 5.8 Hz, 1H), 3.27 (dd, J=10.6, 5.8 Hz, 1H), 1.60 (dt,J=15.2, 8.1 Hz, 1H), 1.54-1.39 (m, 1H), 1.36 (s, 9H), 1.30-1.11 (m, 4H),1.08 (s, 3H), 0.85 (t, J=7.1 Hz, 3H).

Step-7: Preparation of (R)-2-Amino-2-methylhexan-1-ol p-ToluenesulfonicAcid Salt (Compound of Formula VIb)

A reaction vessel was charged with a solution of tert-butyl(R)-(1-hydroxy-2-methylhexan-2-yl)carbamate (1.0 equiv, scaling factor)in methyl tert-butyl ether, and the solvent was exchanged forisopropanol to give a solution at about 6 volumes. The temperature wasadjusted to about 50° C. and a solution of p-toluenesulfonic acid (2equiv) in isopropanol (4 volumes) was charged to the reaction vessel.The contents were agitated for approximately 15 hours at about 50° C.The solvent was exchanged for methyl tert-butyl ether to give a mixtureat about 15 volumes at about 40° C. Crude (R)-2-amino-2-methylhexan-1-olp-toluenesulfonic acid salt (about 0.01 wt %) was charged to thereaction vessel. Methyl tert-butyl ether (5 volumes) was charged to thereaction vessel, and the resulting slurry was agitated for approximately2 hours at about 40° C. The slurry was cooled to about 5° C. andagitated for approximately 12 hours. The slurry was filtered, and thenthe cake was washed with a solution of isopropanol in methyl tert-butylether (1% wt/wt isopropanol in methyl tert-butyl ether), and dried toprovide a compound of Formula VIb. ¹H NMR (400 MHz, DMSO-d₆) δ 7.66 (brs, 3H), 7.49 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.4 Hz, 2H), 5.43 (t, J=4.9Hz, 1H), 3.38 (dd, J=11.2, 4.6 Hz, 1H), 3.33 (dd, J=11.2, 4.8 Hz, 1H),2.29 (s, 3H), 1.57-1.40 (m, 2H), 1.28-1.19 (m, 4H), 1.10 (s, 3H), 0.87(t, J=6.8 Hz, 3H).

Example 9: Preparation of Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate According to theScheme of FIG. 3B (Alternative Method) Step-8: Preparation of Isopropyl(R)-2-amino-2-methylhexanoate N-Ac-Leu Salt

A reaction vessel was charged with N-acetyl-L-leucine (0.8 equiv) and2-methyltetrahydrofuran (10 volumes), and the reaction mixture wasagitated at about 50° C. The reaction vessel was charged with isopropyl2-amino-2-methylhexanoate (1.0 equiv, scaling factor) as a solution in2-methyltetrahydrofuran (10 volumes), and the total volume of thereaction mixture was adjusted to about 25 volumes with additional2-methyltetrahyduran. The reaction mixture was agitated at about 50° C.for approximately 5 hours, and the resulting slurry was cooled to about20° C. over approximately 3 hours and agitated at about 20° C. forapproximately 12 hours. The slurry was filtered, and then the cake waswashed with a mixture of methyl tert-butyl ether and2-methyltetrahydrofuran, and dried. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d,J=8.1 Hz, 1H), 4.89 (hept, J=6.2 Hz, 1H), 4.16 (td, J=8.2, 6.2 Hz, 1H),1.82 (s, 3H), 1.67-1.40 (m, 5H), 1.31-1.21 (m, 3H), 1.21 (s, 3H), 1.19(d, J=6.3 Hz, 6H), 1.15-0.99 (m, 1H), 0.93-0.80 (m, 9H).

Step-9: Preparation of Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate

A reaction vessel was charged with the N-Ac-Leu salt of isopropyl(R)-2-amino-2-methylhexanoate (1.0 equiv, scaling factor), sodiumcarbonate (1.1 equiv) as a solution in water (5 volumes), anddi-tert-butyl dicarbonate (1.05 equiv). The reaction mixture wasagitated at about 20° C. for approximately 15 hours. Methyl tert-butylether (10 volumes) was charged, and the mixture was agitated forapproximately 15 minutes. The phases were allowed to separate, and theaqueous layer was partitioned. Isopropyl(R)-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate was isolated as asolution in methyl tert-butyl ether.

Example 10: Preparation of (R)-2-Amino-2-methylhexan-1-olp-Toluenesulfonic Acid Salt (Compound of Formula VIb) According to theScheme in FIG. 4 Step-10: Preparation of(R)-3-Methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one

A reaction vessel was charged with (R)-2-amino-2-phenylethan-1-ol(scaling factor, 1.0 equiv), molecular sieves (1.5 wt/wt) and2,2,2-trifluoroethanol (10 volumes), followed by ethyl pyruvate (1.05equiv). The mixture was agitated and heated to about 80° C. forapproximately 9 hours. The contents were cooled to about 25° C. andfiltered through diatomaceous earth. The cake was washed with isopropylacetate (3 volumes). The filtrate is concentrated to about 9 volumes andthe solvent is exchanged for isopropanol, targeting approximately 9volumes. The contents were heated to about 40° C., then isopropanol (3volumes) and n-heptane (2 volumes) were charged. The contents were thencooled to about 0° C. over approximately 1.5 hours and aged at thistemperature for approximately 16 hours. The residue was collected,washed with n-heptane (1 volume) and dried to provide(R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one. ¹H NMR (400 MHz,CDCl₃): δ 7.43-7.33 (m, 5H), 4.88-4.83 (m, 1H), 4.57 (dd, J=11.6, 4.5Hz, 1H), 4.31 (t, J=11.6 Hz, 1H), 2.41 (s, 3H).

Step-11: Preparation of (3R,5R)-3-Butyl-3-methyl-5-phenylmorpholin-2-one

A reaction vessel was charged with(R)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (scaling factor,1.0 equiv) and tetrahydrofuran (5 volumes), and the contents were cooledto about −78° C. Boron trifluoride diethyl etherate (2.3 equiv) wascharged over approximately 2 hours, and the contents were agitated underthese conditions for approximately 1 hour. n-Butylmagnesium chloride(2.3 equiv) was charged to the reaction mixture over approximately 4hours. The reaction mixture was aged for approximately 1 hour, thenwarmed to about −55° C. and aged for approximately 1 hour. Water (10volumes) was charged to the reaction vessel, and the mixture was warmedto about 10° C. The reaction vessel was charged with 10 wt % aqueoussodium carbonate (10 volumes) and methyl tert-butyl ether (10 volumes).The mixture was agitated, and then the aqueous layer was partitioned.The organic layer was washed with water (5 volumes) and 20 wt % aqueoussodium chloride (5 volumes). The solvent was exchanged for n-heptanetargeting approximately 7 volumes. The contents were then aged forapproximately 5 hours at about 10° C. The mixture was cooled to about 0°C. over approximately 2 hours, and the slurry was aged at thistemperature for approximately 2 hours. The slurry was filtered; and thenthe cake was washed with n-heptane (2 volumes) and dried to provide(3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one. ¹H NMR (400 MHz,DMSO-d₆): δ 7.46-7.28 (m, 5H), 4.42 (dd, J=9.9, 3.4 Hz, 1H), 4.36-4.30(m, 1H), 4.26-4.20 (m, 1H), 2.88 (d, J=7.2 Hz, 1H), 1.91-1.83 (m, 1H),1.65-1.59 (m, 1H), 1.32-1.27 (m, 7H), 1.32 (t, J=6.9 Hz, 3H).

Step-12: Preparation of(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol

A reaction vessel was charged with(3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one (scaling factor, 1.0equiv) and tetrahydrofuran (16 volumes), and the contents were cooled toabout 0° C. A solution of lithium borohydride in tetrahydrofuran (2.2equiv, 2.0 M in tetrahydrofuran) was charged over approximately 3 hours,and the reaction mixture was aged for approximately 30 minutes. Thereaction mixture was then warmed to about 25° C. and aged forapproximately 9 hours. The mixture was cooled to about 0° C. and 15 wt %aqueous sodium hydroxide (6 volumes) was charged over approximately 4hours. The mixture was warmed to 25° C. and aged at this temperature forapproximately 2 hours. Methyl tert-butyl ether (6.6 volumes) was chargedto the reaction vessel, the mixture was agitated, and the aqueous layerwas partitioned. The organic layer was washed with water (6.6 volumes)and 20 wt % aqueous sodium chloride (6.6 volumes). The solvent wasexchanged for n-heptane targeting approximately 3 volumes. The slurrywas aged at about 15° C. for approximately 1 hour. The slurry wasfiltered and the cake was washed with n-heptane (1 volume) and dried toprovide (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol.¹H NMR (400 MHz, DMSO-d₆): δ 7.37-7.35 (m, 2H), 7.25 (t, J=7.4 Hz, 2H),7.18-7.14 (m, 1H), 5.05-5.03 (m, 1H), 4.36-4.33 (m, 1H), 3.77 (dd,J=9.2, 4.4 Hz, 1H), 3.34-3.33 (m, 1H), 3.22-3.15 (m, 2H), 2.99 (dd,J=10.6, 6.3 Hz, 1H), 1.96 (s, 1H), 1.18-1.12 (m, 3H) 1.08-1.02 (m, 2H),0.93-0.90 (m, 1H), 0.73-0.70 (m, 6H).

Step-13: Preparation of (R)-2-Amino-2-methylhexan-1-ol p-ToluenesulfonicAcid Salt (Compound of Formula VIb)

A reaction vessel was charged with(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol (scalingfactor, 1.0 equiv), ethanol (10 volumes) and p-toluenesulfonic acid(1.50 equiv), and the mixture was agitated. Palladium hydroxide (20% w/won carbon, 0.7% w/w relative to(R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol wascharged. The reaction vessel was purged with nitrogen and charged withhydrogen. The reaction mixture was heated to about 75° C. and aged forapproximately 48 hours. The reaction mixture was filtered, and thefilter cake was washed with ethanol. The filtrate was concentrated toabout 1 volume. Methyl tert-butyl ether (15 volumes) was charged and thecontents were heated to about 60° C. for approximately 2 hours, thencooled to about 0° C. over approximately 3 hours. The slurry wasfiltered and the cake was washed with methyl tert-butyl ether (6volumes) and dried to provide the compound of Formula VIb. ¹H NMR (400MHz, DMSO-d₆) δ 7.66 (br s, 3H), 7.49 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.4Hz, 2H), 5.43 (t, J=4.9 Hz, 1H), 3.38 (dd, J=11.2, 4.6 Hz, 1H), 3.33(dd, J=11.2, 4.8 Hz, 1H), 2.29 (s, 3H), 1.57-1.40 (m, 2H), 1.28-1.19 (m,4H), 1.10 (s, 3H), 0.87 (t, J=6.8 Hz, 3H).

Example 11: Preparation of 3-Bromo-5-fluoropicolinic acid (Compound ofFormula VIIIb) According to the Schemes in FIG. 5A and FIG. 5B Step-14:Preparation of 3-Bromo-5-fluoro-2-iodopyridine

Sodium iodide (4.4 equiv) and acetonitrile (15 volumes) were charged toa reaction vessel and the contents were agitated. The mixture wasazeotropically dried using acetonitrile. The contents were cooled toabout 20° C., and 2,3-dibromo-5-fluoropyridine (1.0 equiv, scalingfactor), water (0.3 equiv) and trimethylsilyl chloride (1.5 equiv) werecharged to the reaction vessel. The contents were agitated at ambienttemperature. The reaction vessel was charged with an aqueous solution of5 wt % sodium hydroxide (5 volumes) and methyl tert-butyl ether (10volumes), the mixture was agitated, and the aqueous layer waspartitioned. The organic solution was washed with 15% aqueous sodiumsulfite, 5 wt % sodium chloride, and water. The organic stream wasconcentrated to approximately 3 volumes. The contents were heated toabout 60° C. and water (5 volumes) was charged over approximately 30minutes. The mixture was aged at about 60° C. for approximately 1 hourand cooled to about 20° C. over approximately 1 hour. The resultingslurry was filtered, washed with a mixture of water and acetonitrile andthe cake was dried to provide 3-bromo-5-fluoro-2-iodopyridine. ¹H NMR(400 MHz, CDCl₃) δ 8.23 (d, J=2.8 Hz, 1H), 7.59 (dd, J=7.6, 2.8 Hz, 1H).

Step-15: Preparation of 3-Bromo-5-fluoropicolinonitrile

Copper(I) cyanide (1.2 equiv), 3-bromo-5-fluoro-2-iodopyridine (1.0equiv, scaling factor) and acetonitrile (10 volumes) were charged to areaction vessel. The contents were agitated and heated to reflux forapproximately 12 hours. The contents were cooled to ambient temperatureand an aqueous solution of sodium thiosulfate (10 volumes) was charged.The contents were aged for approximately 2 hours and then filteredthrough diatomaceous earth and rinsed with methyl tert-butyl ether. Thecombined filtrates were charged to a reaction vessel and the aqueouslayer was partitioned and extracted with methyl tert-butyl ether (5volumes). The organic layer was washed with 5 wt % aqueous sodiumchloride. The solvent was exchanged for isopropanol and concentrated toapproximately 3 volumes. The contents were heated to about 60° C. andwater (7 volumes) is charged over approximately 1 hour. The mixture wasaged at about 60° C. for approximately 30 minutes and cooled to about20° C. over approximately 1 hour. The resulting slurry was filtered, andthe cake was washed with a mixture of isopropanol and water and dried toprovide 3-bromo-5-fluoropicolinonitrile. ¹H NMR (400 MHz, CDCl₃) δ 8.50(d, J=2.5 Hz, 1H), 7.78 (dd, J=7.2, 2.5 Hz, 1H).

Step-16: Preparation of 3-Bromo-5-fluoropicolinic Acid (Compound ofFormula VIIb)

3-Bromo-5-fluoropicolinonitrile (1.0 equiv, scaling factor) andconcentrated sulfuric acid (16.2 equiv, approximately 4 volumes) werecharged to a reaction vessel. The contents were heated to about 50° C.for approximately 2 hours. Water (12.2 equiv, approximately 1 volume)was charged to the reaction vessel and the contents were heated to about90° C. and aged under these conditions for approximately 12 hours. Thecontents were cooled to ambient temperature. To a separate reactionvessel was charged water (20 volumes), and the reaction mixture wastransferred to this vessel over approximately 30 minutes. The resultingmixture was charged with a solution of 45 wt % aqueous potassiumhydroxide (17 equiv) over approximately 30 minutes at about 40° C.Methyl tert-butyl ether (10 volumes) was charged to the reaction vessel,and the contents were heated to about 40° C. The aqueous layer wasextracted with methyl tert-butyl ether. The organic layer was washedwith water and distilled to 3 volumes. Additional methyl tert-butylether was charged and distilled as necessary to azeotropically dry thereaction stream. The contents were heated to about 50° C. and n-heptane(12 volumes) was charged over approximately 1 hour. The contents wereaged under these conditions for approximately 1 hour and cooled to about−20° C. over approximately 3 hours and held at under these conditionsfor approximately 18 hours. The resulting slurry was filtered, and thecake was washed with n-heptane and dried to provide3-bromo-5-fluoropicolinic acid. ¹H NMR (500 MHz, CDCl₃) δ 10.34 (br, s,1H), 8.55 (d, J=2.5 Hz, 1H), 7.93 (dd, J=7.5, 2.5 Hz, 1H).

Step-17: Preparation of 3-Bromo-5-fluoro-2-iodopyridine (AlternativeMethod)

2,3-Dibromo-5-fluoropyridine (1.0 equiv, scaling factor), sodium iodide(2.0 equiv), copper(I) iodide (0.05 equiv),trans-N,N′-dimethylcycloheane-1,2-diamine (0.01 equiv) and 1-butanol (15volumes) were charged to a reaction vessel and the contents wereagitated. The contents were agitated at about 115° C. for approximately20 hours. The contents were cooled to ambient temperature and theorganics were washed with an aqueous solution of 15% aqueous sodiumsulfite, 5 wt % sodium chloride, and water. The organic layer wasfiltered through diatomaceous earth and rinsed with acetonitrile. Thecombined filtrates were charged to a reaction vessel and the solvent wasexchanged for acetonitrile with a target volume of approximately 3volumes. The contents were heated to about 60° C. and water (5 volumes)was charged over approximately 30 minutes. The mixture was aged at about60° C. for approximately 1 hour and cooled to about 20° C. overapproximately 1 hour. The resulting slurry was filtered, washed with amixture of water and acetonitrile and the cake was dried to provide3-bromo-5-fluoro-2-iodopyridine.

Example 12: Preparation of 3-Bromo-5-fluoropicolinic Acid (Compound ofFormula VIIIb) According to the Scheme in FIG. 6 Step-18: Preparation ofN-(tert-Butyl)-5-fluoropicolinamide

Oxalyl chloride (1.1 equiv) was charged over approximately 15 minutes toa reaction vessel containing 5-fluoropicolinic acid (1.0 equiv, scalingfactor) and N,N-dimethylformamide (0.1 equiv) in 2-methyltetrahydrofuran(15 volumes) at about 10° C. The mixture was aged at about 20° C. Thetemperature was adjusted to about 10° C. and tert-butylamine (3.5 equiv)was then charged over approximately 30 minutes. The mixture was aged atabout 20° C. for 2 hours. An aqueous solution of HCl (1 M, 7 volumes)was charged and the mixture was agitated for approximately 15 minutes.The aqueous layer was removed, and the organics were washed with 1Nhydrochloric acid, phosphate buffer solution (1 M, pH=7), and water. Theorganics were exchanged into methylcyclohexane or 1,4-dioxane. Thesolution was filtered to afford N-(tert-butyl)-5-fluoropicolinamide. ¹HNMR (400 MHz, CDCl₃): δ 8.34 (d, J=2.8 Hz, 1H), 8.20 (ddd, J 8.7, 4.7,0.6 Hz, 1H), 7.81 (br s, 1H), 7.50 (ddd, J=8.7, 8.1, 2.8 Hz, 1H), 1.48(s, 9H).

Step-19: Preparation of 3-Bromo-N-(tert-butyl)-5-fluoropicolinamide

A solution of N-(tert-butyl)-5-fluoropicolinamide (1.0 equiv, scalingfactor) in 1,4-dioxane (15 volumes) was charged to a reaction vessel.Di-n-butylmagnesium (1M in heptane, 1.3 equiv) was charged overapproximately 30 minutes. The contents were warmed to about 60° C. andaged at this temperature for about 30 minutes. The contents were cooledto ambient temperature. A separate reaction vessel was charged withmethylcyclohexane (10 volumes) and the contents were cooled to about−20° C. To this solution was charged bromine (2.8 equiv). Then thesolution of metalated N-(tert-butyl)-5-fluoropicolinamide was charged tothe bromine solution in methylcyclohexane over approximately 1 hour andaged for approximately 1 hour at about 20° C. The reaction mixture wascooled to about 5° C. and an aqueous solution of 20% aqueous sodiumsulfite (5 volumes) was charged and the contents were aged forapproximately 30 minutes. The reaction mixture was warmed to about 20°C. Methyl tert-butyl ether (5 volumes) and 1N sodium bisulfate (10volumes) were charged to the reaction vessel, and the contents wereagitated. The aqueous layer was partitioned, and the organics werewashed with water. 3-Bromo-N-(tert-butyl)-5-fluoropicolinamide was thenisolated. ¹H NMR (400 MHz, CDCl₃): δ 8.34 (d, J=2.5 Hz, 1H), 8.34 (dd,J=7.7, 2.5 Hz, 1H), 7.52 (br s, 1H), 1.47 (s, 9H).

The above step-19 reaction can also be performed in methylcyclohexane(19 volumes).

Step-20: Preparation of 3-Bromo-5-fluoropicolinic Acid (Compound ofFormula VIIb)

3-Bromo-N-(tert-butyl)-5-fluoropicolinamide (1.0 equiv, scaling factor),sulfuric acid (4 volumes) and water (2 volumes) were charged to areaction vessel. The contents were heated to about 90° C. The contentswere cooled to about 20° C. and transferred to a second vesselcontaining water (20 volumes). The resulting mixture was charged with asolution of 45 wt % aqueous potassium hydroxide (17 equiv) overapproximately 30 minutes at about 40° C. Methyl tert-butyl ether (10volumes) was charged to the reaction vessel, and the contents wereheated to about 40° C. The aqueous layer was extracted with methyltert-butyl ether. The organic layer was washed with water and distilledto 3 volumes. Additional methyl tert-butyl ether was charged anddistilled as necessary to azeotropically dry the reaction stream. Thecontents were heated to about 50° C. and n-heptane (12 volumes) wascharged over approximately 1 hour. The contents were aged under theseconditions for approximately 1 hour and cooled to about −20° C. overapproximately 3 hours and held at under these conditions forapproximately 18 hours. The resulting slurry was filtered, and the cakewas washed with n-heptane and dried to provide 3-bromo-5-fluoropicolinicacid.

Example 13: Preparation of 2,4-Dichloro-7-fluoropyrido[3,2-d]pyrimidine(Compound of Formula Xb) According to the Scheme of FIG. 7A Step-21:3-Amino-5-fluoropicolinonitrile

A reaction vessel was charged with 2-bromo-5-fluoropyridin-3-amine(scaling factor, 1.0 equiv), tetrakis(triphenylphosphine)palladium(0)(0.015 equiv), N,N-dimethylformamide (5 volumes) and zinc cyanide (0.80equiv). The contents were heated to about 100° C. for approximately 3hours. The mixture was cooled to about 25° C. and filtered throughdiatomaceous earth. The cake was rinsed with N,N-dimethylformamide (1.3volumes) and then the filtrate was charged to a vessel containing asolution of ethylenediaminetetraacetic acid tetrasodium salt (1.5 equiv)and water (10 volumes) over approximately 30 minutes. The mixture washeated to about 40° C. and agitated for approximately 1.5 hours and thencooled to about 20° C. and aged for approximately 2 hours. The slurrywas filtered and the cake was washed with water (1.7 volumes). The cakewas suspended in THE (10 volumes) and filtered. The filtrate wasconcentrated to about 1 volume, and toluene (5 volumes) and DCM (1volume) were charged. The contents were aged for approximately 30minutes. The contents were filtered, and then the cake was washed withtoluene (2 volumes), and dried to provide3-amino-5-fluoropicolinonitrile. ¹H NMR (400 MHz, DMSO-d₆): δ 7.85 (d,J=2.5 Hz, 1H), 7.01 (dd, J=11.0, 2.5 Hz, 1H), 6.59 (br s, 2H).

Step-22: 7-Fluoropyrido[3,2-d]pyrimidine-2,4-diol

A reaction vessel was charged with 3-amino-5-fluoropicolinonitrile(scaling factor, 1.0 equiv), N,N-dimethylformamide (10 volumes) and1,8-diazabicyclo[5.4.0]undec-7-ene (2.2 equiv). The reaction vessel waspurged with a carbon dioxide atmosphere and the contents were heated toabout 50° C. for approximately 24 hours. The mixture was cooled to about40° C. and then charged to a vessel containing 2 N hydrochloride acid(10 volumes) over approximately 1 hour. The mixture was cooled to about20° C. and aged for approximately 1 hour. The mixture was filtered andthe cake was washed with water (5 volumes), isopropanol (5 volumes) andtoluene (5 volumes) successively. The cake was dried to give7-fluoropyrido[3,2-d]pyrimidine-2,4-diol. ¹H NMR (400 MHz, DMSO-d₆): δ11.54 (s, 1H), 11.32 (s, 1H), 8.45 (d, J=2.5 Hz, 1H), 7.34 (dd, J=9.3,2.5 Hz, 1H).

Step-23: 2,4-Dichloro-7-fluoropyrido[3,2-d]pyrimidine (Compound ofFormula Xb)

A reaction vessel was charged with7-fluoropyrido[3,2-d]pyrimidine-2,4-diol (scaling factor, 1.0 equiv),toluene (10 volumes), and N,N-diisopropylethylamine (2.2 equiv).Phosphorus oxychloride (2.5 equiv) was charged to the reaction mixturewhile maintaining the contents below about 35° C. The reaction mixturewas heated to about 110° C. over approximately 2 hours and then held atthis temperature for approximately 18 hours. The reaction mixture wascooled to about 20° C. and charged with dichloromethane (3 volumes). Themixture was charged to a vessel containing a 20 wt % solution of aqueouspotassium phosphate dibasic (10 volumes) while maintaining the contentsbelow about 35° C. The pH of the contents were maintained between 4 to 7by co-dosing a solution of 45 wt % potassium hydroxide. The mixture wasagitated at about 20° C. for approximately 30 minutes, and then theaqueous phase was partitioned. The organic layer was filtered throughdiatomaceous earth and the filter cake was rinsed with toluene (2volumes). The aqueous layer was partitioned, the organic layer wasfiltered through silica gel, and the cake washed with toluene (10volumes). The organic layer was concentrated and the solvent wasexchanged for n-heptane targeting a final volume of about 5 volumes.n-Heptane (4 volumes) and isopropyl acetate (0.74 volumes) were chargedand the contents were heated to about 85° C. and then cooled to about70° C. The crude compound of Formula Xb (0.02 wt %) was charged and thenthe mixture was aged for approximately 45 minutes. The mixture wascooled to about 20° C. over approximately 5 hours and aged forapproximately 18 hours. The mixture was filtered, washed with n-heptane(5 volumes), and dried to give the compound of Formula Xb. ¹H NMR (400MHz, CDCl₃) δ 9.01 (d, J=2.6 Hz, 1H), 7.94 (dd, J=7.8 Hz, 2.4 Hz, 1H).

Example 14: Preparation of 7-Fluoropyrido[3,2-d]pyrimidine-2,4-diolAccording to the Scheme of FIG. 7B (Alternative Method) Step-24:3-Amino-5-fluoropicolinamide

A reaction vessel was charged with 3-amino-5-fluoropicolinonitrile(scaling factor, 1.0 equiv), potassium carbonate (0.2 equiv) anddimethylsulfoxide (4 volumes). The mixture was charged with 30 wt %aqueous hydrogen peroxide (1.2 equiv) while maintaining the internaltemperature below about 40° C., and the contents were agitated forapproximately 1 hour at about 20° C. Water (4 volumes) was charged whilemaintaining the internal temperature below about 40° C. The mixture wascooled to about 20° C. and agitated for approximately 1 hour. The slurrywas filtered, the cake was washed with water (2 volumes), and dried togive 3-amino-5-fluoropicolinamide. ¹H NMR (400 MHz, DMSO-d₆): δ 7.83 (s,1H), 7.71 (d, J=2.5 Hz, 1H), 7.45-7.28 (m, 1H), 6.95 (dd, J=11.3, 2.5Hz, 1H).

Step-25: 7-Fluoropyrido[3,2-d]pyrimidine-2,4-diol

A reaction vessel was charged with 3-amino-5-fluoropicolinamide (scalingfactor, 1.0 equiv) and 1,4-dioxane (5 volumes), and the contents wereheated to about 100° C. The mixture was charged with a solution oftriphosgene (1 equiv) in 1,4-dioxane (5 volumes) over approximately 1hour. The mixture was aged at about 100° C. for approximately 3 hours.The mixture was cooled to about 20° C. The mixture was charged withwater (15 volumes) while maintaining the contents below about 35° C. Themixture was aged at about 20° C. for approximately 1 hour and filtered,and then the cake was washed with water (1 volume) and dried to give7-fluoropyrido[3,2-d]pyrimidine-2,4-diol. ¹H NMR (400 MHz, DMSO-d₆): δ11.54 (s, 1H), 11.32 (s, 1H), 8.45 (d, J=2.5 Hz, 1H), 7.34 (dd, J=9.3,2.5 Hz, 1H).

Example 15: 1-(2,4-Dimethoxybenzyl)guanidine Hemisulfate Salt

Methyl carbamimidothioate hemisulfate salt (1.0 equiv) andN-methyl-2-pyrrolidone (4.4 volumes) was charged to a reaction vessel.The contents were agitated and (2,4-dimethoxyphenyl)methanamine (1.0equiv, scaling factor) was charged to the reaction vessel. The reactionmixture was heated to about 90° C. and agitated at this temperature forapproximately 16 hours. The mixture was cooled to about 0° C. overapproximately 5 hours and aged under these conditions for approximately2 hours. The slurry was filtered and the cake was washed with water (3volumes). The wet cake was combined with ethanol (1.5 volumes) and water(1.5 volumes) and this mixture was aged for approximately 2 hours atabout 20° C. The slurry was filtered and the cake was washed with amixture of ethanol and water and dried to provide1-(2,4-Dimethoxybenzyl)guanidine hemisulfate salt. ¹H NMR (500 MHz,Acetonitrile-d₃) δ 7.61 (t, J=5.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.54(dd, J=8.5, 2.5 Hz, 1H), 6.62 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 3.78 (s,3H), 4.25 (m, 2H).

Example 16: Preparation of(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazoleStep-1: Sodium (R)-2-(3-bromo-5-fluoropicolinamido)-2-methylhexylsulfate

To a reaction vessel containing a solution of(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (1.0equiv, scaling factor) in 2-methyltetrahydrofuran (10 volumes) wascharged acetonitrile (5 volumes) and sulfur trioxide trimethylaminecomplex (2.0 equiv). The contents were heated to about 70° C. Thecontents were aged at this temperature for about 15 hours. Once thereaction is deemed complete, the reaction contents were cooled to about20° C. The resulting mixture was filtered, and the filtrate wastransferred to another reaction vessel. The solution was seeded with thesodium (R)-2-(3-bromo-5-fluoropicolinamido)-2-methylhexyl sulfate and asolution of sodium ethylhexanoate (1.0 equiv) in a 2:1 mixture of2-methyltetrahydrofuran/acetonitrile (4 volumes) was charged over about30 minutes. The mixture was aged for about 2.5 hours after the additionat about 20° C. The contents were filtered, and the resulting solidswere washed with a 2:1 mixture of 2-methyltetrahydrofuran/acetonitrile(5 volumes) and dried at about 50° C. to afford sodium(R)-2-(3-bromo-5-fluoropicolinamido)-2-methylhexyl sulfate. ¹H NMR (400MHz, DMSO-d₆): δ 8.60 (d, J=2.5 Hz, 1H), 8.26 (dd, J=8.5, 2.5 Hz, 1H),8.05 (br s, 1H), 3.90 (d, J=10.0 Hz, 1H), 3.82 (d, J=10.0 Hz, 1H),1.83-1.70 (m, 2H), 1.32-1.21 (m, 4H), 1.32 (s, 3H), 0.88 (t, J=7.0 Hz,3H).

Step-2:(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole

To a reaction vessel was charged sodium(R)-2-(3-bromo-5-fluoropicolinamido)-2-methylhexyl sulfate (1.0 equiv,scaling factor), 2-methyl-2-butanol (15 volumes). The temperature wasadjusted to about 20° C. and then 50 wt % aqueous sodium hydroxide (1.5equiv) was charged to the reaction vessel and the contents were aged forabout 18 hours at about 20° C. Once the reaction is deemed complete, thecontents were diluted in 2-methyltetrahydrofuran (10 volumes) and thenwashed with water (10 volumes) followed by 5 wt % aqueous sodiumchloride (10 volumes). The contents were concentrated to about 5 volumesand polished filtered to provide(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazoleas a solution in a mixture of2-methyl-2-butanol/2-methyltetrahydrofuran. ¹H NMR (500 MHz, CDCl₃): δ8.50 (d, J=2.0 Hz, 1H), 7.76 (dd, J=7.5, 2.5 Hz, 1H), 4.27 (d, J=8.0 Hz,1H), 4.12 (d, J=8.5 Hz, 1H), 1.69-1.43 (m, 3H), 1.42 (s, 3H), 1.36-1.34(m, 3H), 0.92 (t, J=7.0 Hz, 3H).

Example 17: Preparation of(R)-2-(3-Bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole

To a reaction vessel was charged(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (1.0equiv, scaling factor), followed by dichloromethane (2.6 volumes) and4-dimethylaminopyridine (1.2 equiv). The contents were cooled to about0° C. and then para-toluenesulfonyl chloride (1.05 equiv) was added as aslurry in dichloromethane (3.5 volumes) over about 5 minutes. After theaddition, the contents were heated to about 25° C. over about 1 hour.The contents were aged at this temperature for about 5 hours. Then4-dimethylaminopyridine (1.0 equiv) was charged to the reaction vesseland the contents were aged at about 25° C. for about 17 hours. Thecontents were washed twice with a 10 wt % aqueous solution of sodiumhydroxide (5 volumes). Then the contents were washed twice with a 20 wt% aqueous solution of ammonium chloride (5 volumes) and finally washedwith water (5 volumes). The solvent was switched from dichloromethane to2-methyltetrahydrofuran via distillation.(R)-2-(3-Bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazolewas isolated as a solution in 2-methyltetrahydrofuran. ¹H NMR (400 MHz,CDCl₃): δ 8.50 (d, J=2.0 Hz, 1H), 7.76 (dd, J=7.5, 2.5 Hz, 1H), 4.27 (d,J=8.0 Hz, 1H), 4.12 (d, J=8.5 Hz, 1H), 1.69-1.43 (m, 3H), 1.42 (s, 3H),1.36-1.34 (m, 3H), 0.92 (t, J=7.0 Hz, 3H).

Example 18: Preparation of(R)-2-(3-Bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole

To a reaction vessel containing a solution of(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (1.0equiv, scaling factor) in acetonitrile (10 volumes) was charged2,6-lutidine (2.6 equiv). The contents were agitated at about 20° C. Toa separate vessel was charged methanesulfonic anhydride (1.3 equiv) as asolution in acetonitrile (5 volumes). The solution of mathansulfonicanhydride was charged to the solution of(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide and2,6-lutidine over about 30 minutes. After the addition, the contentswere aged for about 15 minutes. The contents were heated to about 50° C.and aged for about 4 hours. When the reaction was deemed complete thesolvent was exchanged to 2-methyltetrahydrofuran (targeting about 10volumes). The contents were cooled to about 20° C. and the organicsolution was washed twice with 20 wt % aqueous ammonium chloride (10volumes) followed by water (10 volumes). The contents were concentratedto about 5 volumes and polished filtered to provide(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazoleas a solution in 2-methyltetrahydrofuran. ¹H NMR (500 MHz, CDCl₃): δ8.50 (d, J=2.0 Hz, 1H), 7.76 (dd, J=7.5, 2.5 Hz, 1H), 4.27 (d, J=8.0 Hz,1H), 4.12 (d, J=8.5 Hz, 1H), 1.69-1.43 (m, 3H), 1.42 (s, 3H), 1.36-1.34(m, 3H), 0.92 (t, J=7.0 Hz, 3H).

Example 19: Preparation of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-olStep-1 and 2:(R)-3,5-Difluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide

Oxalyl chloride (1.1 equiv) was charged over about 30 minutes to areaction vessel containing 3,5-difluoropicolinic acid (scaling factor,1.00 equiv) and N,N-dimethylformamide (0.1 equiv) in2-methyltetrahydrofuran (10 volumes). The mixture was aged at about 20°C. Once the reaction was deemed complete, the acid chloride mixture wastransferred to a second reactor containing(R)-2-amino-2-methylhexan-1-ol 4-methylbenzenesulfonate salt (1.0 equiv)and potassium carbonate (3.0 equiv) in water (10 volumes) over about 30minutes. The biphasic reaction mixture was aged at about 20° C. Once thereaction was deemed complete, the layers were separated, and the organiclayer was washed with water (5 volumes). The organic layer was solventexchanged to 2-methyltetrahydrofuran via distillation and the volume wasadjusted to about 10 volumes.(R)-3,5-Difluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide was thenisolated as a solution in 2-methyltetrahydrofuran. ¹H NMR (400 MHz,CDCl₃): δ 8.31-8.26 (m, 1H), 7.79 (s, 1H), 7.38-7.29 (m, 1H), 3.79 (d,J=11.8 Hz, 1H), 3.73 (d, J=11.8 Hz, 1H), 1.91-1.79 (m, 1H), 1.75-1.63(m, 1H), 1.47-1.21 (m, 7H), 0.99-0.84 (m, 3H).

Step-3 and 4:(R)-4-Butyl-2-(3,5-difluoropyridin-2-yl)-4-methyl-4,5-dihydrooxazole

Thionyl chloride (1.2 equiv) was charged over about 1 hour to a reactionvessel containing a solution of(R)-3,5-difluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (1.0equiv, scaling factor) in 2-methyltetrahydrofuran (10 volumes). Themixture was aged at about 60° C. until the reaction was deemed complete.The contents were adjusted to about 0° C., and the reaction mixture waswashed sequentially with 10 wt % aqueous sodium hydroxide (5 volumes)and water (5 volumes). To the organic solution of(R)—N-(1-chloro-2-methylhexan-2-yl)-3,5-difluoropicolinamide was chargedn-Bu₄HSO₄ (0.1 equiv.), followed by 10 wt % aqueous sodium hydroxide(2.5 volumes). The contents were adjusted to about 20° C. and aged atthis temperature until the reaction was deemed complete. Followingreaction completion, the layers were separated, and the organic layerwas washed with water (5 volumes).(R)-4-Butyl-2-(3,5-difluoropyridin-2-yl)-4-methyl-4,5-dihydrooxazole wasisolated as a solution in 2-methyltetrahydrofuran. ¹H NMR (400 MHz,CDCl₃): δ 8.47-8.41 (m, 1H), 7.32 (ddd, J=9.7, 8.0, 2.4 Hz, 1H), 4.26(d, J=8.3 Hz, 1H), 4.09 (d, J=8.3 Hz, 1H), 1.44-1.20 (m, 7H), 0.94-0.85(m, 3H).

Step-5:(R)-2-((2-((2,4-Dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

A reaction vessel was charged with 2,4-dimethyoxybenzyl guanidinehydrochloride (1.5 equiv) and cesium carbonate (4.0 equiv). A solutionof (R)-4-butyl-2-(3,5-difluoropyridin-2-yl)-4-methyl-4,5-dihydrooxazole(1.0 equiv, scaling factor) in 2-methyltetrahydrofuran (7.5 volumes) wascharged to the reactor. The reaction mixture was heated to about 80° C.Once the reaction was deemed complete the contents were cooled to about35° C. and charged with water (10 volumes). The layers were separated,and the organics were washed sequentially with aqueous 5 wt % aceticacid (10 volumes) and water (10 volumes). The contents were concentratedto about 2 volumes. Isopropyl acetate (10 volumes) was charged and thecontents were concentrated to about 5 volumes. The contents wereadjusted to about 35° C. The resulting slurry was aged for about 1 hourat about 35° C., then cooled to about 20° C. over about 1.5 hours. Thecontents were aged at about 20° C. for about 1 hour. The contents werefiltered and washed with a mixture of n-heptane and isopropyl acetateand dried to provide(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol.¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, J=2.5 Hz, 1H), 7.32-7.29 (m, 2H),7.10 (br s, 1H), 6.47 (d, J=2.53 Hz, 1H), 6.43 (dd, J=8.2, 2.4 Hz, 1H),4.55 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79-3.72 (m, 2H), 2.01-1.91(m, 1H), 1.75 (dt, J=13.3, 6.8 Hz, 1H), 1.47-1.29 (m, 7H), 0.92 (t,J=7.0 Hz, 3H).

Example 20: Preparation of(R)-2-((2-(benzylamino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

A reaction vessel was charged with 1-benzylguanidine (1.5 equiv) andcesium carbonate (2.0 equiv). A solution of 2,4-dimethyoxybenzylguanidine hydrochloride (1.0 equiv, scaling factor) in2-methyltetrahydrofuran (7.5 volumes) was charged to the reactor. Thereaction mixture was heated to about 80° C. Once the reaction was deemedcomplete the contents were cooled to about 35° C., charged with water(10 volumes) and the contents were agitated. The phases were separated,and the organics were washed sequentially with aqueous 5 wt % aceticacid (10 volumes) and water (10 volumes). The contents were concentratedto about 2 volumes. Isopropyl acetate (10 volumes) was charged and thecontents were concentrated to about 5 volumes. The contents wereadjusted to about 35° C. The resulting slurry was aged for about 1 hourat about 35° C., then cooled to about 20° C. over about 1.5 hours. Thecontents were aged at about 20° C. for about 1 hour. The contents werefiltered and washed with a mixture of n-heptane and isopropyl acetateand dried to provide(R)-2-((2-(benzylamino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol.¹H NMR (400 MHz, CDCl₃): δ 8.16 (d, J=2.5 Hz, 1H), 7.40-7.26 (m, 5H),7.13 (br s, 1H), 4.70-4.60 (m, 2H), 3.80-3.72 (m, 2H), 1.98-1.86 (m,1H), 1.78-1.66 (m, 1H), 1.48-1.19 (m, 7H), 0.91 (t, J=7.0 Hz, 3H).

Example 21: Preparation of(R)-2-((2-Amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

A pressure autoclave reaction vessel was charged with(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol(1.0 equiv, scaling factor), 10% dry palladium on carbon (0.125 g/g) andformic acid (5 volumes). The vessel was sealed and flushed with hydrogenthree times. The hydrogen pressure was adjusted to about 85 psi and thecontents were heated to about 85° C. and aged for about 18 hours. Thecontents were then cooled to about 20° C. and the vessel was vented andflushed three times with nitrogen. The reaction mixture was thenfiltered thought a pad of Celite (0.5 g/g) and the reaction vessel wasrinsed with formic acid (1 volume). The filtrate was transferred toanother reaction vessel. Water (5 volumes) and ethanol (2.5 volumes)were charged to the contents. The temperature was adjusted to about 20°C. and 50 wt % aqueous sodium hydroxide (14.5 volumes) was added slowlyto maintain the internal temperature to about 35° C. The contents wereaged for about 16 hours at about 20° C. The slurry was filtered, and thewet cake was washed with a mixture of ethanol and water and dried toprovide(R)-2-(3-bromo-5-fluoropyridin-2-yl)-4-butyl-4-methyl-4,5-dihydrooxazole.¹H NMR (500 MHz, Methanol-d₄) δ 8.23 (d, J=2.5 Hz, 1H), 7.25 (dd,J=10.0, 2.5 Hz, 1H), 3.92 (d, J=11.5 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H),2.08-1.81 (m, 2H), 1.46 (s, 3H), 1.35-1.29 (m, 4H), 0.91 (t, J=7.0 Hz,3H).

Example 22: Preparation of(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

A reaction vessel was charged with(R)-3-bromo-5-fluoro-N-(1-hydroxy-2-methylhexan-2-yl)picolinamide (1.0equiv, scaling factor), 3 Å molecular sieves (1 g/g) and acetonitrile(6.7 volumes). 1-(2,4-dimethoxybenzyl)guanidine hemisulfate salt (1.5equiv), copper(I) iodide (0.10 equiv), 2,2′-bipyridine (0.20 equiv),potassium phosphate tribasic (3.5 equiv) and 3 Å molecular sieves (1g/g) were then charged to the vessel. The mixture was heated to refluxfor about 3 hours. The contents were cooled to about 20° C., chargedwith 2-methyltetrahydrofuran (5 volumes), followed by water (5 volumes).The phases were separated, the organics were concentrated, and the crudeproduct was purified using silica gel chromatography to provide(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol.¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, J=2.5 Hz, 1H), 7.32-7.29 (m, 2H),7.10 (br s, 1H), 6.47 (d, J 2.53 Hz, 1H), 6.43 (dd, J=8.2, 2.4 Hz, 1H),4.55 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.79-3.72 (m, 2H), 2.01-1.91(m, 1H), 1.75 (dt, J=13.3, 6.8 Hz, 1H), 1.47-1.29 (m, 7H), 0.92 (t,J=7.0 Hz, 3H).

Example 23: Preparation of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

A reaction vessel was charged with guanidine sulfate (1.5 equiv), cesiumcarbonate (2.0 equiv). A solution of(R)-4-butyl-2-(3,5-difluoropyridin-2-yl)-4-methyl-4,5-dihydrooxazole(1.0 equiv, scaling factor) in dimethylacetamide (5 volumes) was chargedto the reactor. The reaction mixture was heated to about 80° C. Once thereaction was deemed complete the contents were cooled to about 35° C.,charged with water and 2-methyltetrahydrofuran. The phases wereseparated, the organics were concentrated, and the crude material waspurified by silica gel chromatography to provide(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol.¹H NMR (500 MHz, Methanol-d₄) δ 8.23 (d, J=2.5 Hz, 1H), 7.25 (dd,J=10.0, 2.5 Hz, 1H), 3.92 (d, J=11.5 Hz, 1H), 3.74 (d, J=11.5 Hz, 1H),2.08-1.81 (m, 2H), 1.46 (s, 3H), 1.35-1.29 (m, 4H), 0.91 (t, J=7.0 Hz,3H).

Example 24: Preparation ofN-(4-(tert-butylamino)-7-fluoropyrido[3,2-d]pyrimidin-2-yl)acetamide

A reaction vessel was charged with palladium(II) acetate (0.10 equiv),followed by a solution of 1,3-bis(dicyclohexylphosphino)propane (0.2equiv) in toluene (5 volumes). To the vessel was charged2-bromo-3,5-difluoropyridine (1.0 equiv, scaling factor) andtert-butylisocyanide (1.1 equiv). Then N-acetyl guanidine (2.0 equiv)was charged to the reaction vessel, followed by cesium carbonate (2.6equiv). The contents were heated to about 90° C. and aged for about 24hours. The contents were cooled to about 20° C. and the contents werefiltered through a plug of silica gel eluting with ethyl acetate. Thecrude product was concentrated and purified using silica gelchromatography to provideN-(4-(tert-butylamino)-7-fluoropyrido[3,2-d]pyrimidin-2-yl)acetamide. ¹HNMR (400 MHz, CDCl₃): δ 8.32 (d, J=2.6, 1H), 7.92 (br s, 1H), 7.49 (dd,J=9.4, 2.6 Hz, 1H), 7.12 (br s, 1H), 2.58 (s, 3H), 1.53 (s, 9H).

Example 25: Preparation of(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol

A reaction vessel is charged with palladium(II) acetate (0.10 equiv),followed by a solution of 1,3-bis(dicyclohexylphosphino)propane (0.2equiv) in toluene (5 volumes). To the vessel is charged2-bromo-3,5-difluoropyridine (1.0 equiv, scaling factor) and(R)-isocyano-2-methylhexan-1-ol (1.1 equiv). Then guanidine hemisulfate(2.0 equiv) is charged to the reaction vessel, followed by cesiumcarbonate (3.6 equiv). The contents are heated to about 90° C. and areagitated for about 24 hour. The contents are cooled to about 20° C. andthe contents are filtered through a plug of silica gel eluting withethyl acetate. The crude product is concentrated and purified usingsilica gel chromotography to provide(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol.

Example 26: Preparation of Isopropyl 2-amino-2-methylhexanoate Step 1:2-Amino-2-methylhexanenitrile

To a reaction vessel was charged sodium cyanide (1.0 equiv, scalingfactor), magnesium sulfate (1.8 equiv), ammonium chloride (0.5 equiv)and ammonia in methanol (7 M, 3.0 equiv, 9 volumes). The contents werecooled to about 0° C. and 2-hexanone (1.1 equiv) was charged to themixture. The contents were aged at this temperature for about 30minutes. Then the contents were warmed to about 35° C. Once the internaltemperature reached about 35° C., the contents were aged at thistemperature for about 4 hours. The contents were then cooled to about20° C., diluted with methyl tert-butyl ether (5 volumes) and thecontents were concentrated. The residue was suspended in methyltert-butyl ether (10 volumes) and concentrated once again. This processwas repeated one more time. The contents were suspended in methyltert-butyl ether (10 volumes) and filtered. The filter cake was washedwith methyl tert-butyl ether (2 volumes) and the filtrate wasconcentrated to an oil. The oil was purified via vacuum distillation toafford 2-amino-2-methylhexanenitrile. ¹H NMR (400 MHz, CDCl₃) δ1.65-1.57 (m, 2H), 1.50-1.42 (m, 2H), 1.44 (s, 3H), 1.40-1.34 (m, 2H),0.92 (t, J=7.2 Hz, 3H).

Step 2: Isopropyl 2-amino-2-methylhexanoate

To a reaction vessel was charged 2-amino-2-methylhexanenitrile (1.0equiv, scaling factor) and 2-propanol (10 volumes). The contents werecooled to about 20° C. To this solution was charged 15 wt % aqueoussulfuric acid (10 equiv). The contents were heated to about 80° C. andaged at this temperature for about 36 hours. The contents were cooled toabout 20° C. and 2-methyltetrahydrofuran (20 volumes) was charged. Tothe contents was charged 50 wt % aqueous sodium hydroxide (about 15equiv) until the pH of the aqueous solution was basic. The aqueous layerwas partitioned. The organic layer was washed twice with water (2volumes) and the contents were distilled to provide isopropyl2-amino-2-methylhexanoate as a solution in 2-methyltetrahydrofuran. ¹HNMR (400 MHz, DMSO-d₆) δ 4.86 (hept, J=6.3 Hz, 1H), 1.68 (br s, 2H),1.59-1.48 (m, 1H), 1.47-1.35 (m, 1H), 1.24-1.19 (m, 4H), 1.16 (d, J=6.3Hz, 6H), 1.14 (s, 3H), 0.83 (t, J=7.1 Hz, 3H).

Example 27: Preparation of (R)-2-Amino-2-methylhexan-1-ol4-methylbenzenesulfonate Step-1 and 2: (R)-2-Amino-2-methylhexanoic AcidHydrochloride

To reaction vessel was chargedtert-butyl-2-(4-chlorobenzylidene)amino)propanoate (1.0 equiv, scalingfactor) and toluene (10 volumes). To this solution was charged1-bromobutane (1.33 equiv) and N-benzylcinchoninium chloride (0.10equiv), followed by potassium hydroxide (2.4 equiv) and potassiumcarbonate (0.97 equiv). The mixture was aged at about 20° C. for about17 hours. The organic solution was then washed twice with water (4volumes x 2) followed by saturated aqueous sodium chloride (4 volumes).The organic layer was concentrated. To this crude material was charged2-propanol (12 volumes) and the contents were concentrated once again.To this mixture was charged 5 N hydrochloric acid in 2-propanol (3volumes) and water (1.2 equiv). The contents were aged at about 60° C.for about 4 hours. The contents were concentrated to about 2 volumes. Tothis mixture was charged 2-propanol (1 volume) and methyl tert-butylether (1 volume) and the contents were slowly cooled to about 20° C.over about 4 hours. To this slurry was charged methyl tert-butyl ether(3 volumes) and the contents were aged at about 20° C. for about 18hours. The slurry was filtered, and the wet cake was rinsed with amixture of 2-propanol (1 volume) and methyl tert-butyl ether (2volumes). The resulting solids were triturated with toluene (10volumes). The slurry was filtered, and the wet cake was washed withtoluene (10 volumes) and then dried to provide(R)-2-amino-2-methylhexanoic acid hydrochloride. ¹H NMR (400 MHz,DMSO-d₆) δ 8.55 (br s, 3H), 2.50-1.74 (m, 2H), 1.43 (s, 3H), 1.41-1.14(m, 5H), 0.83 (t, J=6.8 Hz, 3H).

Step-3: (R)-2-Amino-2-methylhexanoic acid hydrochloride

To a reaction vessel was charged (R)-2-amino-2-methylhexanoic acidhydrochloride (1.0 equiv, scaling factor), water (5 volumes) and 5 Naqueous sodium hydroxide (3.5 equiv). The contents were cooled to about5° C. and then the solution was charged with benzoyl chloride (2.5equiv). The contents were warmed to about 15° C. and aged for about 6hours. The aqueous mixture was washed twice with dichloromethane (10volumes x 2). To the aqueous layer was charged 6 N aqueous hydrochloricacid until the pH of the solution was acidic (about pH 2). The resultingslurry was filtered and washed with 0.1 N aqueous hydrochloric acid (6volumes). The wet cake was dried to provide(R)-2-benzamido-2-methylhexanoic acid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.25(br s, 1H), 8.22 (s, 1H), 7.87-7.80 (m, 2H), 7.56-7.50 (m, 1H),7.49-7.43 (m, 2H), 2.00-1.87 (m, 1H), 1.79 (dt, J=15.8, 7.0 Hz, 1H),1.43 (s, 3H), 1.34-1.18 (m, 4H), 0.78 (t, J=6.9 Hz, 2H).

Step-4: (R)-2-Amino-2-methylhexan-1-ol 4-methylbenzenesulfonate

To a reaction vessel was charged (R)-2-benzamido-2-methylhexanoic acid(1.0 equiv, scaling factor) and tetrahydrofuran (5 volumes), and thenthe contents were cooled to about 0° C. Once at this temperature 1 Mborane tetrahydrofuran complex in tetrahydrofuran (5 equiv) was chargedover about 5 minutes. The contents were warmed to about 25° C. and agedat this temperature for 10 minutes. Then the contents were heated toabout 50° C. and aged at this temperature for about 21 hours. Thecontents were cooled to about 20° C. and methanol (5 volumes) wascharged. The contents were heated to about 100° C. and the contents wereconcentrated to about 8 volumes. This process of co-evaporation withmethanol was repeated two more times. The contents were set to refluxand 1 M aqueous sodium hydroxide (12 volumes) was charged. The contentswere refluxed for about 4 hours. Then the contents were cooled to about20° C. and methyl tert-butyl ether (15 volumes) was charged. The layerswere separated, and the organic layer was washed with 5 wt % aqueoussodium chloride (15 volumes). The layers were separated, and the organiclayer was concentrated to provide the crude benzylamine intermediate,which was used in the next step without further purification.

To the crude benzylamine intermediate was charged ethanol (10 volumes)and 4-methylbenzenesulfonic acid (1.50 equiv), followed by palladiumhydroxide (20% w/w on carbon, 0.7% w/w relative to(R)-2-benzamido-2-methylhexanoic acid). The reaction vessel was purgedwith nitrogen and charged with hydrogen. The reaction mixture was heatedto about 75° C. and aged for about 48 hours. When the reaction wasdeemed complete, the reaction mixture was filtered, and the filter cakewas washed with ethanol. The filtrate was concentrated to about 1volume. Methyl tert-butyl ether (15 volumes) was charged and thecontents were heated to about 60° C. for about 2 hours, then cooled toabout 0° C. over about 3 hours. The slurry was filtered, and the solidswere washed with methyl tert-butyl ether (6 volumes) and dried toprovide (R)-2-amino-2-methylhexan-1-ol 4-methylbenzenesulfonate. ¹H NMR(400 MHz, DMSO-d₆) δ 7.66 (br s, 3H), 7.49 (d, J=8.1 Hz, 2H), 7.12 (d,J=7.4 Hz, 2H), 5.43 (t, J=4.9 Hz, 1H), 3.38 (dd, J=11.2, 4.6 Hz, 1H),3.33 (dd, J=11.2, 4.8 Hz, 1H), 2.29 (s, 3H), 1.57-1.40 (m, 2H),1.28-1.19 (m, 4H), 1.10 (s, 3H), 0.87 (t, J=6.8 Hz, 3H).

Example 28: Preparation of (R)-2-Amino-2-methylhexan-1-ol4-methylbenzenesulfonate

To a reaction vessel was charged (R)-2-amino-2-methylhexanoic acidhydrochloride (1.0 equiv, scaling factor) and tetrahydrofuran (7volumes). The contents were cooled to about 0° C. and lithium aluminumhydride (4 equiv) was charged. The contents were heated to about 60° C.and aged at this temperature for about 3 hours. After this amount oftime, the contents were cooled to about 0° C. and water (5 volumes) wascharged. The contents were aged at this temperature for 30 minutes andwarmed to about 20° C. To the contents was charged 15 wt % aqueoussodium hydroxide (3 volumes) and the contents were aged for anadditional 30 minutes. The aqueous layer was extracted withdichloromethane (10 volumes). This was repeated three more times. Thecombined organic layers were concentrated to dryness. The crude(R)-2-amino-2-methylhexan-1-ol 4-methylbenzenesulfonate was diluted inethanol (10 volumes) and filtered into another reaction vessel. To thisfiltrate was charged 4-methylbenzenesulfonic acid (1 equiv) and thecontents were aged at about 25° C. for about 30 minutes. The contentswere concentrated to dryness and co-evaporated with methyl tert-butylether (10 volumes). This process was repeated one more time. Theresulting solids were filtered, and the solids were washed with methyltert-butyl ether (2 volumes) and dried to provide(R)-2-amino-2-methylhexan-1-ol 4-methylbenzenesulfonate. ¹H NMR (400MHz, DMSO-d₆) δ 7.66 (br s, 3H), 7.49 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.4Hz, 2H), 5.43 (t, J=4.9 Hz, 1H), 3.38 (dd, J=11.2, 4.6 Hz, 1H), 3.33(dd, J=11.2, 4.8 Hz, 1H), 2.29 (s, 3H), 1.57-1.40 (m, 2H), 1.28-1.19 (m,4H), 1.10 (s, 3H), 0.87 (t, J=6.8 Hz, 3H).

Example 29: Preparation of (R)-2-amino-2-methylhexanoic acidhydrochloride Step-1:(2S,4R)-3-Benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one

To a reaction vessel was charged(2S,4R)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one (1.0 equiv, scalingfactor) and tetrahydrofuran (8 volumes), followed byhexamethylphosphoramide (4 volumes). The contents were then cooled to−78° C. To this solution was charged a 1 M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran (1.1 equiv) and the contentswere aged at this temperature for about 15 minutes. Then 1-iodobutane(1.5 equiv) was charged as a solution in tetrahydrofuran (2 volumes).The contents were aged at about −78° C. for about 3 hours. The contentswere then warmed to about 25° C. and aged at this temperature for about21 hours. After this amount of time, the contents were quenched withsaturated aqueous ammonium chloride (5 volumes). The contents wereconcentrated to remove tetrahydrofuran, dichloromethane (10 volumes) wascharged, and the aqueous layer was extracted. This process was repeatedtwo more times. The combined organic extracts were combined andconcentrated to dryness. The crude product was purified by columnchromatography using ethyl acetate and hexanes to provide(2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one. ¹H NMR (400MHz, CDCl₃) δ 7.56-6.88 (m, 10H), 6.74 (s, 1H), 1.97-1.75 (m, 2H), 1.43(s, 3H), 1.32-1.18 (m, 5H), 0.78 (t, J=6.8 Hz, 2H).

Step-2: (R)-2-amino-2-methylhexanoic Acid Hydrochloride

To a reaction vessel was charged(2S,4R)-3-benzoyl-4-butyl-4-methyl-2-phenyloxazolidin-5-one (1.0 equiv,scaling factor) followed by concentrated hydrochloric acid (7 volumes).The contents were heated to about 90° C. and aged at this temperaturefor about 4 hours. The contents were cooled to about 20° C. and dilutedwith water (10 volumes). The solvent was exchanged for toluene undervacuum (targeting approximately 1 volume). Then the contents weresuspended using 2-propanol (1 volume) and methyl tert-butyl ether (2volumes) and filtered. The resulting solids were triturated with toluene(10 volumes). The slurry was filtered, and the wet cake was washed withtoluene (10 volumes) and dried to provide (R)-2-amino-2-methylhexanoicacid hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (br s, 3H),2.50-1.74 (m, 2H), 1.43 (s, 3H), 1.41-1.14 (m, 5H), 0.83 (t, J=6.8 Hz,3H).

Although the foregoing disclosure has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

1.-73. (canceled)
 74. A method for preparing a compound of Formula II:

or a salt thereof, comprising: a) forming a first reaction mixturecomprising a compound of Formula V:

a compound having the Formula PG-NHC(═NH)NH₂ or a salt thereof, a firsttransition-metal catalyst, a first base, and a first solvent to form thecompound of Formula II, a salt thereof, wherein R¹, R², and R³ are eachindependently hydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴is hydrogen or methyl; R⁵ is C₃₋₆ alkyl; X is F, Cl, Br, I, or OTs; andPG is an amino protecting group.
 75. The method of claim 74, wherein PGis 2,4-dimethoxybenzyl. 76.-79. (canceled)
 80. A compound of FormulaIII:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; and X is F, Cl, Br, I, or OTs.
 81. A compoundof Formula IV:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; X is F, Cl, Br, I, or OTs; and AG¹ is Cl, Br,OSO₃H, OSO₃ ⁻, OMs, OTs, or OTf.
 82. A compound of Formula V:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; R⁴ is hydrogen ormethyl; R⁵ is C₃₋₆ alkyl; and X is F, Cl, Br, I, or OTs, provided thatthe compound of Formula V is not3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.
 83. Acompound of Formula XII:

or a salt thereof, wherein R¹, R², and R³ are each independentlyhydrogen, F, Cl, CN, CF₃, C₁₋₃ alkyl, or C₁₋₃ alkoxy; and R⁶ and R⁷ areeach independently hydrogen, C₁₋₄ alkyl, or C₃₋₆ cycloalkyl, or R⁶ andR⁷ are combined to form a 3-6 membered N-linked heterocycloalkyl,optionally having an additional 1-2 heteroatoms selected from O and S,provided that at least one of R¹, R², and R³ is F, Cl, CN, CF₃, C₁₋₃alkyl, or C₁₋₃ alkoxy.
 84. The compound of claim 83, wherein R¹ and R³are each hydrogen; R² is F; R⁶ is hydrogen; and R⁷ is tert-butyl.85.-113. (canceled)